TYPE 1 DIABETES A very special issue

Volume 56 – December 2011
TYPE 1 DIABETES
A very special issue
SPECIAL ISS U E
Global perspectives on diabetes
47
6
DiabetesVoice
32
43
Contents
Diabetes Views
4
T h e g l o b a l i m pa c t
International Diabetes Federation
Promoting diabetes care, prevention and a cure worldwide
Estimating the worldwide burden of type 1 diabetes
6
Diabetes Voice is published quarterly and is freely available
online at www.diabetesvoice.org.
Hope springs for young people with type 1 diabetes
9
The production of this Special Issue has been made possible
thanks to the support of Sanofi Diabetes.
The 3-C Study – strong partnerships to improve care
for people with type 1 diabetes in China
13
Leonor Guariguata
Graham Ogle and Larry Deeb
Linong Ji and Helen McGuire
m a n a g e m e n t, c a r e a n d p r e v e n t i o n
The key to managing diabetes without tears – the treatment and
teaching programme for flexible insulin therapy in Germany
16
Ulrich Alfons Müller
Taking the benefits of DAFNE to the UK and beyond
19
Stephanie A Amiel, Julia Lawton, Simon Heller
Positive results in Australia – OzDAFNE takes up the challenge
22
Never say never – implementing DAFNE in Kuwait
24
Dianne Harvey
Ebaa Alozairi
Great results for DAFNE Singapore – next stop, South-East Asia
27
Making progress with immune therapies for type 1 diabetes
29
Su-Yen Goh and Daphne Gardner
Mark Peakman
All that glitters is not gold – why we need better trials and reporting 32
Rury R Holman
Back to the future: investigating new treatments for type 1 diabetes
using old inexpensive drugs
37
Denise Faustman and Miriam Davis
c a u s e s a n d e ff e c t s
From victim to protector – what the brain does with hypoglycaemia 40
Stephanie A Amiel
Epilepsy in children and adolescents with type 1 diabetes
43
Edith Schober and Reinhard Holl
diabetes champions
Breakthrough – the story of Elizabeth Hughes and
the making of a medical miracle
45
Arthur Ainsberg
In the race for a glittering prize – Team Type 1 hits the road
Phil Southerland
47
This publication is also available in French, Spanish
and Chinese.
Editor-in-Chief: Stephanie A Amiel, UK
Managing Editor: Olivier Jacqmain, [email protected]
Editor: Tim Nolan, [email protected]
Advisory group: Pablo Aschner (Colombia),
Ruth Colagiuri (Australia), Patricia Fokumlah (Cameroon),
Attila József (Hungary), Viswanathan Mohan (India).
Layout and printing: Luc Vandensteene, Ex Nihilo, Belgium,
www.exnihilo.be
All correspondence and advertising enquiries should be
addressed to the Managing Editor:
International Diabetes Federation, Chaussée de La Hulpe 166,
1170 Brussels, Belgium
Phone: +32-2-5431626 – Fax: +32-2-5385114 – [email protected]
© International Diabetes Federation, 2010 – All rights reserved.
No part of this publication may be reproduced or transmitted
in any form or by any means without the written prior permission of the International Diabetes Federation (IDF). Requests
to reproduce or translate IDF publications should be addressed
to the IDF Communications Unit, Chaussée de La Hulpe 166,
B-1170 Brussels, by fax +32-2-5385114, or by e-mail
at [email protected]
The information in this magazine is for information purposes only.
IDF makes no representations or warranties about the accuracy and
reliability of any content in the magazine. Any opinions expressed
are those of their authors, and do not necessarily represent the views
of IDF. IDF shall not be liable for any loss or damage in connection
with your use of this magazine. Through this magazine, you may
link to third-party websites, which are not under IDF’s control.
The inclusion of such links does not imply a recommendation or
an endorsement by IDF of any material, information, products and
services advertised on third-party websites, and IDF disclaims any
liability with regard to your access of such linked websites and use of
any products or services advertised there. While some information
in Diabetes Voice is about medical issues, it is not medical advice and
should not be construed as such.
ISSN: 1437-4064
Cover photo © Wong Sze Yuen - istockphoto.com
From diabetes education and prevention all the way to sporting
excellence – Italy’s BCD Campaign
49
Massimo Massi-Benedetti
December 2011 • Volume 56 • Special Issue 2
DiabetesVoice
3
Diabetes views
A very special
issue in a
stellar year
for diabetes
the diabetes pandemic that
maximizes the resources
available to tackle the causes
and consequences of the
upsurge in type 2 diabetes and prioritizes the needs of people
with type 1 diabetes. The diagnosis, treatment and management
of non-preventable diabetes require integrated health systems,
delivery of care down to primary
care level and supportive policies
outside the health sector.
The 5th edition of the IDF Diabetes Atlas, which was launched on
World Diabetes Day, 14 November 2011, presented some daunting
figures: the estimated number of adults living with diabetes has
soared to 366 million – more than 8% of the global adult population
– and is projected to rise to 552 million people by 2030 – just
short of 10% of all adults. That means that diabetes is growing at
the extraordinary rate of approximately three new cases every 10
seconds. The Atlas estimates confirm that diabetes continues to
affect disproportionately the socially disadvantaged and continues
to increase especially rapidly in low- and middle-income countries
– where the health system is already ill equipped to provide care
and resources for people with any type of diabetes.
While type 2 diabetes dominates in sheer numbers, type 1 diabetes
remains a very special issue. With 70,000 newly diagnosed young
people every year, the prevalence of type 1 diabetes is growing
globally – not just in northern Europe. Those affected have very
particular needs. The bottom line could not be more crude: unless
they are diagnosed quickly and then receive insulin and skilled
instruction on how to use it, people with type 1 diabetes die very
quickly. That adults and children should be dying every day because
they go undiagnosed or do not have access to insulin is deplorable.
In various partnerships with other non-profit groups and public
and private entities IDF is working to bridge some of the gaps.
IDF’s child sponsorship programme, Life for a Child, supports
services for children with diabetes and their families in resourcepoor communities worldwide. And in collaboration with the
International Society for Pediatric and Adolescent Diabetes
(ISPAD), IDF has produced the brand new Guideline for Diabetes
in Childhood and Adolescence – which covers all diabetes in young
people. The desired role of the guideline is not only to assist
individual healthcare providers in managing young people with
diabetes; it aims to improve awareness among governments and
state healthcare providers of the essential resources needed for
optimal care.
These activities are vital and our involvement can only increase.
But our fight for diabetes will take us further – beyond the diabetes
community. Societies in general must build a concerted response to
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DiabetesVoice
In terms of our campaign to
achieve those long-term objectives,
2011 has been a landmark year for
diabetes. In September, I attended
an historic meeting of world leaders
at the UN Summit, where they adopted the first ever Political
Declaration on Non-Communicable Diseases. The standard bearer
for diabetes throughout, IDF has been a principal figure in the
NCD Alliance largely responsible for that historic accomplishment
in New York. And we are among the ‘NCD revolutionaries’ – as
described recently by Richard Horton, Editor of The Lancet – who
are striving to ensure that the promises made by governments can
be turned into action for people with diabetes of any type.
Diabetes needs the reach, the voice and the power to generate
government interest in health-protective policies beyond the health
sector – and then to actually legislate for them. A broad coalition
of aligned groups will be fundamental; inter-sectoral alliance is
a significant recommendation of the 2011 Political Declaration.
IDF provides the platform for that much needed collaboration.
IDF engages in ‘triple p partnerships’ (public-private-people) that
bring together non-health actors and key stakeholders, including
the private sector where appropriate, and civil society in proactive
partnerships to promote and protect health.
As we look forward to a new year and welcome a new springtime
in the fight against diabetes, we must act as a global community.
We are all part of the solution!
Jean Claude Mbanya is IDF President for
the period 2009 to 2012. He is Professor
of endocrinology at the University of
Yaounde, Cameroon, and Chief of the
Endocrinology and Metabolic Diseases
Unit at the Hospital Central in Yaounde.
December 2011 • Volume 56 • Special Issue 2
Diabetes views
Type 1 diabetes:
quo vadis?
In this special issue of Diabetes Voice, there is a focus on type
1 diabetes. In tackling the world pandemic of diabetes, and
the critical importance of making societal change to arrest the
staggering rise in the prevalence of type 2 diabetes, it is easy for
the needs of the 10% of people with diabetes who have type 1
diabetes to be forgotten. Yet incidence of type 1 diabetes is also
rising – at 3% per year (see page 6) - and as Professor M'Banya
points out in his editorial, people with type 1 diabetes worldwide
are still dying because of missed diagnoses or inadequate insulin
supply. The disease particularly affects children: IDF estimates that
there are over half a million children with type 1 diabetes currently.
But another danger exists in forgetting that type 1 diabetes can
arise at any age and that focusing attention only on children may
disenfranchise adults living with the disease. Be they children or
adults, the needs of the people with type 1 diabetes are different
from those of the majority of people with diabetes and have to be
be addressed separately.
As exemplified by this special issue, IDF has not forgotten the
10%. At our international meeting in Dubai, IDF presented data
on type 1 diabetes in China from a collaboration that started in
July, in partnership with the Chinese Diabetes Society and insulin
manufacturers Sanofi Aventis, sponsors of this issue of Diabetes
Voice. We are excited that this issue of Diabetes Voice is published
in Mandarin.
It is now 90 years since the discovery of insulin. One of the
remarkable things about the insulin story is how quickly it moved
from bench to bedside – one might be forgiven for wondering
how it would have fared in today’s regulatory environment! It
is sobering to reflect that the first recipient of insulin – Leonard
Thompson – died of pneumonia in the era before the discovery of
antibiotics. On page 45, Thea Cooper and Arthur Ainsberg review
the history of the discovery of insulin from the perspective of one
of the people whose life it saved – touching also on the limitations
of insulin as a therapy. Since Elizabeth Hughes received her first
insulin injection, we have learned much about how to use insulin
most appropriately – now we need to learn how to transfer that
information to our colleagues – and to our patients. And we need
the funding to do it effectively.
As with any long-term condition, and certainly as with other forms
of diabetes, the best – indeed the only – person who can properly
manage the disease is the person who lives with it, day by day, month
by month, year by year. It is the role of the healthcare professional to
equip the patient (and often their family) with the tools to do this.
This is much more than a prescription for insulin and blood glucose
monitoring equipment. Good outcomes also need the users of these
December 2011 • Volume 56 • Special Issue 2
items – which,
although they are
essential, are not
easy to come by for
everyone – to have a high degree of knowledge and enough
confidence to apply that knowledge and the emotional security
to be able to handle it all. Providing that support takes time –
another commodity not always in great supply – and expertise,
from healthcare professionals as well as people with diabetes.
Helping our patients to learn how to manage their life on insulin
injections is too important to leave to chance or to random, wellmeaning interventions of unproven validity. It needs resourcing. On
pages 16 to 28, we look at the globalization of one strategy for helping
people with type 1 diabetes to live more healthily, using structured
education to help patients use insulin flexibly. The Dusseldorf
DAFNE programme can help people with type 1 diabetes achieve
the glucose targets that reduce the risk of complications, while
reducing hypoglycaemia risks and allowing people to live the life
they choose with measurable benefit to quality of life. It is founded in
well-validated principles of insulin action and educational strategies
that work for adults, and has a good evidence base for its efficacy.
Delivering such programmes requires skilled healthcare professionals
who understand education as well as physiology and metabolism.
The need for an expert multidisciplinary team has never been
stronger. Developing such programmes for children and adolescents,
who require different educational approaches, has been slow but is
evolving. Many throughout the diabetes community will be keeping
an eye out for future developments. I have no doubt that the editors
of this special issue would like to hear of successes in this area!
Access to good therapy for people with type 1 diabetes should not
be a lottery. Nor should it be dependent upon charitable works
and humanitarian organizations. Health organizations, in trying to
reduce costs by re-structuring services for people with other forms
of diabetes, must not allow the support needed by people with type
one to be the baby that gets thrown out with the bath-water!
Professor Sir K George M M Alberti
Chairman of Diabetes UK and
Past-President of IDF
DiabetesVoice
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Diabetes views
Estimating the
worldwide burden
of type 1 diabetes
Leonor Guariguata
Providing an accurate estimate of the number of children with type 1
diabetes is an essential component of planning health policy, assessing
the quality of care and driving research. There is good evidence that
the incidence of type 1 diabetes among children is increasing in many
parts of the world. The International Diabetes Federation’s Diabetes
Atlas, 5th edition, estimates that increase to be 3% per year. The
cause of this rise is unknown, although it may be linked to a number
of factors. Studies have found associations with older mothers, early
exposure to dietary components, such as cow’s milk, and a reduction
in the frequency of early infections. Many of these factors can be
linked to socioeconomic development and changes in environments.
However, there are important geographic differences in the trends,
which may reflect underlying differences in ethnicity, exposure to
potential risk factors and the capacity of health systems to identify
and record people diagnosed with type 1 diabetes. Leonor Guariguata
reports on the global status of type 1 diabetes in children and looks
at some the key issues behind the latest figures.
Type 1 diabetes is one of the most common endocrine and metabolic conditions among children. According to the
latest edition of the Diabetes Atlas, an
estimated 490,100 children below the
age of 15 years are living with type 1
diabetes.1 A further 77,800 children under the age of 15 are expected to develop
the disease in 2011 and there is evidence
6
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that the incidence is rising rapidly, especially among the youngest children.2-4
Type 1 diabetes is increasing steeply
in some central and eastern European
countries, where the disease remains less
common than in other regions.5 If these
trends continue, it is inevitable that the
total prevalence of people with type 1
diabetes will increase in coming years.
Regional trends
An estimated 24% of all children with
type 1 diabetes live in the European
region, where the most reliable and
up-to-date estimates of the burden of
diabetes are available. Two large international collaborative projects, the
Diabetes Mondiale study (DiaMond)
and the Europe and Diabetes study
(EURODIAB) have been instrumental
in monitoring developments in the incidence of type 1 diabetes in children,
providing us with some of the best evidence on trends and prevalence for any
region. These studies have shown that
the rate of new cases in many countries
is highest among younger children.2
In many countries, the
rate of newly diagnosed
type 1 diabetes
is highest among
younger children.
There are a number of clinical implications for this overall drop in the ages
at which young people are being diagnosed with type 1 diabetes. Diagnosis
December 2011 • Volume 56 • Special Issue 2
THE GLOBAL IMPACT
in a young child may be delayed or
missed because of subtle and misleading symptoms. In many cases, it can be
impossible for a child to be stabilized
and begin receiving care outside hospital – which, in many parts of the world,
presents a serious barrier to seeing a
qualified health professional. Moreover,
younger children with diabetes may be
more likely than their older peers to
present with ketoacidosis at the time of
diagnosis and may face more years of
hyperglycaemia with increased risk of
complications. These combined factors
place a significant burden on health systems and may increase the costs of care.
Europe is followed closely by SouthEast Asia, with 23% of the world’s young
people with type 1 diabetes, and North
America and the Caribbean, with 19%.
However, the lack of data in other parts
of the world makes it difficult to estimate
the true burden. In sub-Saharan Africa
and many low-resource countries, diagnosis may be missed and children may
December 2011 • Volume 56 • Special Issue 2
be dying from a lack of insulin before
they are identified. One study in Sudan
showed a mortality rate of 42.6 deaths
per 100,000 children with type 1 diabetes.6 This is compared to 0.63 deaths per
100,000 children with type 1 diabetes
in the USA.7 It is almost impossible to
determine the true incidence and prevalence in these regions; special efforts
must be made to record and report on
this problem. Regardless, even in studies
from high-income countries, children
with type 1 diabetes had at least twice
the mortality rate of children without
the disease.8
Even in high-income
countries, children with
type 1 diabetes died at
twice the rate of children
without the disease.
Mortality
This early mortality is almost certainly
linked to a severe lack of access to insulin
and quality care. A study by the
International Insulin Foundation, the
Rapid Assessment Protocol for Insulin
Access, conducted in five countries (Mali,
Mozambique, Nicaragua, Vietnam, and
Zambia), found several barriers to access
to good care, including a lack of availability of quality insulin, syringes, and
monitoring devices.9 These barriers pose
a direct threat to children with type 1
diabetes, who must rely on caregivers to
help manage their disease and obtain the
materials necessary to keep them alive.
A number of other factors can have a
strong influence on estimates of type 1
diabetes. For older children moving into
adolescence, distinguishing between
type 1 diabetes and type 2 diabetes becomes more difficult; problems of misclassification can hamper efforts to estimate accurately the status of diabetes.
Type 2 diabetes is emerging as a serious
problem for adolescents worldwide. As a
result, children who present with type 2
diabetes, a disease traditionally associated
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THE GLOBAL IMPACT
with adults, may be misclassified as having type 1 diabetes. Similarly, as global trends in obesity also increase in
children and adolescents, some young
people who are obese but present with
type 1 diabetes may be misclassified as
having type 2 diabetes because of the
latter’s strong links with obesity.10
Generating the figures
All the estimates and figures produced
by IDF and published in the Diabetes
Atlas are based on studies carried out
in regions and countries. For the 5th
edition, a total 88 studies were used to
generate the estimates for diabetes in
children. The majority of those studies were carried out in Europe, North
America and South-East Asia. There
are serious gaps in the availability of
studies from sub-Saharan Africa and
parts of the Western Pacific, which influences the figures for those regions.
The quality and reliability of studies can
vary greatly depending on the methods used and the representation of the
population. Most of the studies used for
global estimates draw on population-
based diabetes registries, which record
newly diagnosed people with diabetes.
These numbers are then used to estimate the prevalence of type 1 diabetes
in children.
The Atlas reports type 1 diabetes estimates only for children between 0 and
14 years – and no older – because the
majority of studies include this information. There are few studies estimating
the burden of type 1 diabetes among
young people aged between 15 and 19,
and even fewer capturing estimates for
type 1 diabetes in adults. However, there
is some indication that in high-income
countries, between 10% and 15% of all
diabetes is attributable to type 1 diabetes,
while the estimate is likely to be lower
in low- and middle-income countries.
The way forward
Despite gaps in the evidence and the
need for more high-quality studies, it
is clear that type 1 diabetes is a serious
health priority all over the world. It is
essential to map the disease in order to
set priorities for care and improve the
life of people with type 1 diabetes, including, perhaps especially, the children
with diabetes and their families through
improved access to medicines, social
support and diabetes education. With
type 1 diabetes on the rise in many parts
of the world, resources must be developed to meet the needs of this growing
population.
Leonor Guariguata
Leonor Guariguata is biostatistician at
the International Diabetes Federation.
References
1 I nternational Diabetes Federation.
Diabetes Atlas, 5th ed. IDF. Brussels, 2011.
2 T
uomilehto J, Virtala E, Karvonen M, et al.
Increase in incidence of insulin-dependent
diabetes mellitus among children in Finland.
Int J Epidemiol 1995; 24: 984-92.
3 G
ardner SG, Bingley PJ, Sawtell PA, et al.
Rising incidence of insulin dependent diabetes
in children aged under 5 years in the Oxford
region: time trend analysis. The Bart’s Oxford
Study Group. BMJ 1997; 315: 713-7.
4 D
ahlquist G, Mustonen L. Analysis of 20
years of prospective registration of childhood
onset diabetes time trends and birth cohort
effects. Swedish Childhood Diabetes Study
Group. Acta Paediatr 2000; 89: 1231-7.
5 E
URODIAB ACE Study Group. Variation
and trends in incidence of childhood diabetes
in Europe. Lancet 2000; 355: 873-6.
6 E
lamin A, Altahir H, Ismail B, Tuvemo
T. Clinical pattern of childhood type 1
(insulin-dependent) diabetes mellitus in
the Sudan. Diabetologia 1992; 35: 645-8.
7 N
ishimura R, LaPorte RE, Dorman JS, et al.
Mortality Trends in Type 1 Diabetes: The
Allegheny County (Pennsylvania) Registry
1965-1999. Diabetes Care 2001; 24: 823-7.
8 I nternational Diabetes Federation. Diabetes
Atlas, 3rd ed. IDF. Brussels, 2007.
9 B
eran D, Yudkin JS, de Courten M. Access
to care for patients with insulin-requiring
diabetes in developing countries: case
studies of Mozambique and Zambia.
Diabetes Care 2005; 28: 2136-40.
10 Rosenbloom AL, Silverstein JH, Amemiya S,
et al. Type 2 diabetes mellitus in the child and
adolescent. Pediatric Diabetes 2008; 9: 512-26.
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December 2011 • Volume 56 • Special Issue 2
THE GLOBAL IMPACT
Hope springs for
young people with
type 1 diabetes
Graham Ogle and Larry Deeb
The IDF Diabetes Atlas,
5 edition, estimates that
th
worldwide 495,100 children
below 15 years of age are living
with diabetes. Added to this
number would be as many or
more young people aged between
15 and 25 years. Together with
adults with type 1 diabetes, these
1 million plus children and young
people face the challenge of living
with a complex, life-threatening
chronic disease, but in widely
different circumstances. The
authors reflect on the latest
figures from around the world
for type 1 diabetes in young
people, describe some of the
challenges to providing universal
care and treatment, and deliver
good news about some positive
trends in the developing world.
December 2011 • Volume 56 • Special Issue 2
In the developed world, the outlook for
a child with type 1 diabetes has changed
dramatically over the 90 years since insulin was discovered. The diagnosis used
to be a death sentence, with life expectancy measured in months. As reported
elsewhere in this issue, there have been
steady advances since then, including:
longer-acting animal insulin, blood
glucose self-monitoring, HbA1c testing,
understanding of complications and the
importance of blood glucose control,
appreciation of the role of different diets
and exercise regimens, human insulin,
diabetes education and empowerment
(including associations of people with
diabetes and diabetes camps), the multidisciplinary team, analogue insulins and
insulin pump therapy. In parallel with
this, scientific understanding of immunological and pathological mechanisms
and determination of best-practice care
have occurred.
Extensive research is underway into
all dimensions of type 1 diabetes, with
much attention focused on closing the
loop between blood glucose measurement and insulin delivery, prediction
and prevention, and possibilities for a
cure, such as islet cell transplantation.
Nowadays, many people live with type 1
diabetes for 60 or 70 years, or more,
and long-term studies of adults who
developed diabetes during childhood
show steady reductions in mortality
rates with time, with the likelihood that
this will continue to improve.1
More than a quarter
of a million children
with type 1 diabetes
– 50% of the global
population – live in the
developing world.
Examination of the Diabetes Atlas figures reveals interesting details. Incidence
varies markedly around the world and,
on average, is increasing at between 3%
and 4% per year.2,3 Of the estimated
495,100 children with type 1 diabetes,
around 230,000 (some 46%) live in
developed countries – the European
nations, USA and Canada, Australia,
New Zealand, Japan, Singapore, Saudi
Arabia, and other high-income nations.
The remaining 260,000 children with
diabetes live in middle- and low-income
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THE GLOBAL IMPACT
countries. India is estimated to have
97,700 and China 8,700 (reflecting the
stark difference in measured incidence
between these two countries). Africa has
an estimated 36,000 cases.
10
(particularly in Africa) – presumably
due to high mortality rates. In others
(for instance in Central America), the
incidence may be considerably higher
than the few studies (often relatively
old) would suggest.
These estimates are the best that can be
made with the available data. However,
there are, by necessity, many extrapolations where there are gaps in the data;
129 of the 202 countries listed have no
incidence data. For a number of others,
the data are relatively old and determined from a region or city rather than
the whole country.
Lack of access to
insulin, limited medical
expertise and education,
and extreme poverty
combined lead to very
poor outcomes.
Even when the rate of incidence is
known, prevalence is very difficult
to calculate in poor countries, as few
have a complete registry or any published information on mortality rates.
Direct experience of the IDF Life for
a Child programme suggests that the
Atlas may markedly overestimate the
existing numbers in some countries
Children in high-income countries have
access to comprehensive care – the most
up-to-date and complete range of health
technologies that can be offered to people with diabetes with the aim of achieving best possible outcomes. In many
middle-income countries and some
low-income countries, quality care is
also achieved - through well-designed
cost-effective approaches consistent
DiabetesVoice
with available resources. However, there
are number of countries, particularly in
sub-Saharan Africa but also in Asia and
the Americas, where such care is only
available to wealthy families.
Lack of access to, and the high cost
of, insulin and other supplies, limited
health professional expertise concerning childhood diabetes, lack of diabetes
education, geographic isolation and extreme poverty can result in very poor
outcomes – starting with frequent misdiagnosis at disease onset so the child
dies untreated; then a high risk of early
death from hypoglycaemia or ketoacidosis; and for those who survive, very
poor blood glucose control. Such sustained poor control leads to impaired
quality of life – many children drop out
of school, cannot find employment or
a marriage partner and develop severe
complications (such as loss of vision,
end-stage renal failure and severe neuropathy) in their 20s or even earlier.
December 2011 • Volume 56 • Special Issue 2
THE GLOBAL IMPACT
In the last 10 years, however, progress
has been made in some low-income
countries concerning access to insulin
for children and adolescents. Various
factors are helping this trend: economic
growth in some countries, more market
competition, the availability of reduced
prices to developing nations in certain
circumstances and the impact of Life for
a Child and other programmes (which
receive and deploy donated supplies).
There is an alarming
trend in at least a few
countries towards
purchasing analogue
and other expensive
insulin preparations.
However, many children do not receive
enough insulin and have insecure, intermittent access, particularly in outlying
and rural areas of developing countries,
and in developing countries that have
not yet been able to develop a diabetes
service.
Self-monitoring of blood glucose is also
beyond the reach of many thousands of
children and adolescents with diabetes, as neither their government health
system nor their own family’s finances
can afford to buy test strips – which,
paradoxically, are more expensive than
insulin. Transnational solutions are urgently needed in this area. Further challenges occur in the availability of HbA1c
testing and screening for complications,
such as for microalbuminuria.
Equal to the problem of access to insulin and other supplies is the lack of
available diabetes education in many
countries. Few physicians are familiar
with childhood diabetes, and children
are often treated by adult internists or
general practitioners. Many countries
December 2011 • Volume 56 • Special Issue 2
have no specialty diabetes nurse educators. Skills and settings to educate
families and young people affected by
diabetes are lacking, and often there
are no education materials available.
Diversity of languages and educational
levels compound the challenges.
However, we can report with pleasure
that the situation is changing. The diabetes landscape is being transformed by
the dedicated efforts of local champions – doctors and non-medical people
determined to make childhood diabetes
a focus – combined with support from
the international diabetes community
(health professionals, developed-country associations, industry).
We can report with
pleasure that the
situation is changing;
a watershed has
been reached for
care of childhood
diabetes worldwide.
For instance in Mali, the intervention
of Santé Diabète and the Government
health services, with support from the
Life for a Child Program, has led to
dramatic improvements in survival. In
Mali in 2007, only 14 young people aged
below 23 years were known to the diabetes community. With the provision
of adequate insulin, test strips, HbA1c
testing equipment and other supplies,
this number has risen to more than 140
– most of the increase being new cases.
Mortality rates are now low. Similarly,
in Rwanda, there are improvements in
care4 and sharp increases in numbers.
Life for a Child is supporting diabetes
services in 36 countries and has developed a website for childhood and
adolescent diabetes education resources
in major world languages. A range of
other initiatives is also underway: the
International Society for Pediatric
and Adolescent Diabetes (ISPAD) is
conducting training and developing
guidelines; the Changing Diabetes in
Children programme is assisting diabetes centres in a number of countries; and
the International Insulin Foundation is
working to improve access to supplies.
There is an increasing emphasis on
training paediatric endocrinologists, including the successful ISPAD/European
Society of Paediatric Endocrinology
School in Nairobi, Kenya.
Very much more remains to be done.
However, due to the coordinated collaborative efforts of the international
diabetes community to effect change, a
watershed has been reached for care of
childhood diabetes worldwide.
Graham Ogle and Larry Deeb
Graham Ogle is a paediatric endocrinologist.
He is General Manager of the IDF Life for a
Child programme and Director of Health and
Social Services at HOPE worldwide (Australia).
Larry Deeb is Clinical Professor of Pediatrics
at the University of Florida and Clinical
Professor of Behavioral Medicine at Florida
State University, USA. He is also the chair
of the IDF Task Force for Insulin, Test
Strips, and other Diabetes Supplies.
References
1 S ecrest AM, Becker DJ, Kelsey SF, et al. All-cause
mortality trends in a large population-based
cohort with long-standing childhood-onset type 1
diabetes. Diabetes Care 2010; 33: 2573-9.
2 D
IAMOND Project Group. Incidence and
trends of childhood Type 1 diabetes worldwide
1990-1999. Diabet Med 2006; 23: 857-66.
3 P
atterson CC, Dahlquist GG, Gyurus E, et al.
Incidence trends for childhood type 1 diabetes
in Europe during 1989-2003 and predicted
newcases 2005-20: a multicentre prospective
registration study. Lancet 2009; 373: 2027-33.
4 M
arshall SL, Sharma, V, Ogle G, Orchard T.
Improvements of Glucose Control Seen in
Children with Type 1 Diabetes in Rwanda, Africa.
Diabetes 2011; 60(Suppl1): Abstract 1165-P, A320.
DiabetesVoice 11
Diabetes view from the field
CDS facing down
challenges to
improved care
for type 1
diabetes
Despite these
efforts, many
unmet needs
remain.
Discrimination against
people with type 1
diabetes is still common,
for instance. People with
type 1 diabetes face great
difficulties accessing higher
education and employment.
This social unfairness
not only has a negative impact on personal lives, it hinders
disease management. For example, in order to hide their
condition, many students and employees with type 1
diabetes never test blood glucose and inject insulin at school
or the work place, making intensive glucose control impossible.
China is experiencing an increase in the number of people with
type 1 diabetes. New cases as well as improved life expectancy
among people with established diabetes are behind the rising
prevalence. The incidence of type 1 diabetes among children has
been put at 0.59 per 100,000 people per year. Although this is far
lower than in some other regions, such as northern Europe, our
numbers are huge because China has such a large population – in
excess of 1.3 billion.
The Chinese Diabetes Society (CDS) is dedicated to improving
diabetes care for people with type 1 diabetes through education
and good clinical practice. CDS members have organized a national
programme to train medical professionals in the management of
type 1 diabetes. The CDS Guideline for diagnosis and treatment of
diabetic ketoacidosis in childhood type 1 diabetes and Consensus of
insulin treatment in childhood type 1 diabetes were developed in
2009 and 2010, respectively.
CDS has made education one of its priorities. A CDS task-force,
which was founded in 2003, focuses on enhancing and extending
training for diabetes educators and certifying those who are
qualified. Educators play more and more important roles in diabetes
management, especially in improving people’s ability to follow
professional diabetes management advice.
Beijing Children’s Hospital is a good example. In the past five
years, the educator at that hospital designed a structured course
covering contents from fundamental survival skills to advanced
self-management. Following structured education, blood glucose
control has improved dramatically among young people with diabetes
at the centre. Many tertiary care centres in large cities organize
summer camps for children with type 1 diabetes and their parents,
providing activities that teach kids with type 1 diabetes and their
parents how to cope with the disease, and giving the children the
confidence they need to fight the disease, safe in the knowledge
that they are not alone.
12
DiabetesVoice
Special care for people with type 1 diabetes is available only in the
large clinical centres located in major cities. The type 1 diabetes
management capabilities of primary and secondary healthcare
centres are still very limited. Even in the larger clinics, standards of
care for type 1 diabetes have not been well implemented throughout.
Moreover, the way in which people with type 1 diabetes are identified
remains an area for serious attention. There are multiple reports of
misdiagnoses of type 1 diabetes leading to fatalities.
The personal financial burden of disease management is high. For
example, throughout most of the country, glucose test strips and
disposable insulin pen lancets are not reimbursed. As a result,
people with type 1 diabetes reportedly are using the disposable
needles for several days.
CDS is fully committed to ongoing efforts to promote standards of
care and education to improve the life of young people with type
1 diabetes. We will continue to work closely with the government
and other sectors of society to improve quality of life and welfare
of all people with the condition in China.
Linong Ji, Director of the Department of
Endocrinology and Metabolism Peking
University People’s Hospital and President
of the Chinese Diabetes Society
December 2011 • Volume 56 • Special Issue 2
THE GLOBAL IMPACT
The 3-C Study – strong
partnerships to improve
care for people with
type 1 diabetes in China
Helen McGuire and Linong Ji
In March 2010, investigators
from the Chinese Diabetes
Society (CDS) published a
study that captured headlines
in the popular as well as the
medical media around the
world. It estimated that the
number of people with diabetes
in China had risen in excess
of 92 million. With the release
of those findings, China took
over from India the dubious
mantle of diabetes capital of the
world. The authors look at the
epidemiological contribution of
type 1 diabetes to the national
and global figures, and present
a major new study aimed
ultimately at improving care for
people with the disease in China.
December 2011 • Volume 56 • Special Issue 2
On World Diabetes Day this year,
14 November 2011, the 5th edition of
the International Diabetes Federation
Diabetes Atlas was released containing
the estimate that 8,700 children under
14 years of age in China have type 1
diabetes – an incidence rate of 0.6 per
100,000 per year.1 Although the prevalence and incidence rates are relatively
low in China, the number of people with
type 1 diabetes represents more than
half the total number of young people
with type 1 diabetes in the Western
Pacific Region.
In 2000, a large study was conducted
over several countries including China
that looked at trends in the incidence and
prevalence of type 1 diabetes in children
14 and under.2 Within China, the highest incidence was found in the region of
Wuhan (4.6 per 100,000 per year) and
lowest in Zunyi (0.1 per 100000 per year).
Incidence was highest in children aged
between 10 and 14 years of age, and there
was no statistically significant genderbased difference in the rate.
Opportunities exist to
achieve earlier diagnosis
and strengthen
secondary prevention
efforts in China.
Recent studies in China on clinical presentation and outcomes of people with
type 1 diabetes suggest that opportunities exist to achieve earlier diagnosis
and strengthen secondary prevention
efforts. A 2007 study found that children under 18 years of age in China
had generally poorer outcomes than
the average values of young people in 11
countries in the Western Pacific Region
(Figure).3 Severe hypoglycaemia was
DiabetesVoice 13
THE GLOBAL IMPACT
the exception, with a regional average of 74 events per 100 patient years
compared with 39 events per person
years in China. A more recent study,
carried out in Shenyang found that 41%
of children with type 1 diabetes present
with ketoacidosis and that the average
duration of symptoms before going to
hospital was 24.5 days.4
Type 1 diabetes in China is an important
area for research due to the paucity of
available data. Moreover, investigating type 1 diabetes has the potential
to influence the changing healthcare
environment in China to improve care
and clinical outcomes for people with
the disease throughout the country.
IDF is active in building the global
diabetes evidence base and advocating for improved care for people with
diabetes. An umbrella organization of
more than 200 national diabetes associations around the world, IDF represents
the interests of the growing number of
people with diabetes and those at risk.
Leading the global diabetes community
since 1950, IDF’s mission is to promote
diabetes care, prevention and a cure
worldwide. IDF collaborates with its
Member Associations to support their
efforts to advance their strategic priorities and transfer knowledge from one
region of the world to another.
In 2009, IDF conceived a project to assess the current status of care, including
the costs involved in coverage for people
with type 1 diabetes, in order to influence change and ultimately improve
outcomes for people with diabetes. IDF
and Sanofi agreed to work together to
realize a timely and innovative type 1
diabetes research project.
and CDS was contacted to determine
their interest. A Member Association
of IDF founded in 1991, CDS conducts
various public education programmes,
epidemiological surveys and research in
China. The mission of CDS is to prevent
and treat diabetes and provide information to help educate people living
with diabetes, their families, healthcare
professionals and the public about this
disease. Led by IDF and with CDS collaboration and Sanofi support, the triparty partnership was formed.
The network of
participating healthcare
facilities is a testament
of the power of effective
partnerships.
To advance the project design, the IDF
specialist team, Helen McGuire, David
Whiting and Katia Skarbek travelled
to China on several occasions to meet
with stakeholders and refine the protocol to match local realities. Professors
Linong Ji (in Beijing) and Weng (in
Shantou) represented CDS, and, along
with IDF, led the establishment of the
project in China. An academic research
organization in China was contracted
to assist with implementation in Beijing
and Shantou.
The potential strength of partnerships
became clear as the IDF team worked
closely with healthcare professionals
and investigators in China to launch
the project. CDS brought together a
network of 19 committed hospitals and
primary health centres to participate
in the project. These include: Peking
University People's Hospital, Military
Hospital, Peking Union Hospital, Beijing
Children's Hospital, Peking University
First Hospital, Peking University Third
Hospital, Beijing Haidian Hospital, the
Luhe Teaching Hospital of the Capital
Medical University, Pinggu Hospital,
Zhanlan Road Community Health
Service Centre, the Second Hospital
of Tongzhou district, Pinggu Town
Community Health Service Centre,
Pingguoyuan Community Health
Service Centre, the First Affiliated
Hospital of Shantou University Medical
College, the Second Affiliated Hospital
of Shantou University Medical College,
Chaonan Minsheng Hospital, Chenghai
under
n with type 1 diabetes
re
ild
ch
in
es
m
co
ut
O
Figure:
vs 11 countries in the
18 years of age in China3
n
Western Pacific Regio
WPR
HbA1c
Microalbuminuria
Hypertension
8.8%
2.5%
21.6%
China
9.5%
13.0%
23.9%
China was identified as the appropriate country to launch such a project
14
DiabetesVoice
December 2011 • Volume 56 • Special Issue 2
THE GLOBAL IMPACT
Huaqiao Hospital, Chaonan Longtian
Health Service Centre, Chenghai Dongli
Health Service Centre. This comprehensive network of committed healthcare
facilities is a testament of the power of
effective partnerships.
This global-to-local
partnership represents
an important model
for advancing diabetes
care worldwide.
In July 2011, the 3-C Study: Coverage,
Cost and Care of Type 1 Diabetes in
China5 was launched in Beijing at a
press conference featuring Jean Claude
Mbanya, IDF President, Linong Ji, CDS
President and Riccardo Perfetti, Vice
President of Global Medical Affairs,
Diabetes Division, Sanofi. The globalto-local partnership achieved in this
project represents an important model
for advancing diabetes care worldwide:
National member associations provide
in-country expertise and networking
IDF provides the global perspective
and facilitates knowledge transfer from
one region of the world to another
Industry makes a positive contribution to the advancement of care by
supporting organizations to develop
and implement projects without interference from the funder.
The 3-C Study will provide data to inform policy and decisions on the advancement of treatment of type 1 diabetes in China. Its key objectives are
as follows:
Describe coverage, cost and care for
type 1 diabetes
Estimate the number of people with
type 1 diabetes
Estimate the economic burden from
type 1 diabetes and financial barriers
to care
December 2011 • Volume 56 • Special Issue 2
Training session for study investigators in Shantou
I dentify the scale of government investment needed to improve healthcare coverage
Define the burden of disease in terms
of clinical outcomes
Describe the educational and care experiences of people with type 1 diabetes compared with selected clinical
practice guidelines
Describe the information processes
associated with diabetes care and education.
This is the first research initiative to
study a chronic disease from a range
of angles. The model established and
experience gained in this study will be
invaluable in studying other chronic
conditions, such as type 2 diabetes. The
gaps identified between what should be
happening in type 1 diabetes care and
day-to-day reality will lay the foundations for future translational research
into the implementation of care standards for people with type 1 diabetes in
China.
The tri-party partnership led by IDF has
achieved a culturally relevant and scalable project. With 366 million people in
the world living with diabetes and many
questions about the disease unanswered,
such collaborations are vital. We must
speak with a common voice if we are
going to make a real difference.
Helen McGuire and Linong Ji
Helen McGuire is Senior Diabetes
Education and Health Systems
Specialist at IDF and a member of the
IDF team leading the 3-C Study.
Linong Ji is Director of the Department
of Endocrinology and Metabolism at
Peking University People’s Hospital,
Beijing, People’s Republic of China.
References
1 I nternational Diabetes Federation. Diabetes
Atlas 5th edition. IDF. Brussels, 2011.
2 Y
ang Z, Wang K, Li T, et al. Childhood diabetes
in China. Enormous variation by place and
ethnic group. Diabetes Care 1998; 21: 525-9.
3 C
raig ME, Jones TW, Silink M, Ping
YJ. Diabetes care, glycemic control, and
complications in children with type 1 diabetes
from Asia and the Western Pacific Region.
J Diabetes Complications 2007; 21: 280-7.
4 X
in Y, Yang M, Chen XJ, et al. Clinical features
at the onset of childhood type 1 diabetes
mellitus in Shenyang, China.
J Paediatr Child Health 2010; 46: 171-5.
5 M
cGuire H, Kissimova-Skarbek K,
Whiting D, Ji L. The 3C Study: Coverage
cost and care of type 1diabetes in China –
Study Design and Implementation. Diab
Res Clin Pract 2011; Doi:10.1016.
DiabetesVoice 15
MANAGEMENT, CARE AND PREVENTION
The key to managing
diabetes without tears –
the treatment and
teaching programme
for flexible insulin
therapy in Germany
Ulrich Alfons Müller
Successful implementation of structured
education programmes that teach people with type
1 diabetes to use insulin flexibly around normal
lifestyle behaviours is the subject of this and
the following four articles in this special issue.
Programmes such as the UK's Dose Adjustment
for Normal Eating (DAFNE), in which the person
affected by type 1 diabetes is central to all
disease management decisions, are the object of
a number of projects in different countries. While
such programmes are increasingly regarded
as the state-of-the-art deployment of diabetes
resources, their origins lay in Germany early
in the last century. Ulrich Müller looks back at
the birth and initially arrested development of
flexible insulin therapy programmes, describes
the approach itself and demonstrates what
makes it an optimum therapeutic approach.
16
DiabetesVoice
It was the paediatrician, Karl Stolte, who, using pre-meal
urine tests to target insulin dose adjustment, first provided
people affected by diabetes with education to adapt their
insulin regimen to be able to eat normally. 1 His idea to
increase the dose of soluble (regular) insulin to allow
dietary freedom came in 1928, when a birthday cake was
brought to a hospital ward for a child without diabetes and
shared with eight children with the disease. His work and
his conviction that “people with diabetes should not eat
like laboratory animals, which day after day get food calculated down to the gram” were rejected by most German
paediatricians and diabetologists at the time – and until
as late as the 1980s!
The first diabetes teaching unit in a European country was
founded by Jean Philippe Assal at the University Hospital
in Geneva, Switzerland, in 1970. A paradigmatic change
was underway in theories about diabetes therapy. ‘Patient
education’, which took the form of obedience training,
was replaced by an approach based on empathy, empow-
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
erment and autonomy. In 1979, the Diabetes Education
Study Group of the European Association for the Study of
Diabetes was founded. Its major goal was to make skills
and knowledge training for effective disease management
an integral part of any affected person’s diabetes therapy.
The emphasis for people with type 1 diabetes was on a
five-day inpatient treatment and teaching programme in
groups of 6 to 10 people.
A paradigmatic change was underway
in theories about diabetes therapy.
A structured programme – development and evaluation
Between 1980 and 1990, Michael Berger and his team at
the University of Düsseldorf developed the original Geneva
programme for general use in Germany. The overarching
objective was to provide education, skills training and
motivation that could enable people with diabetes to take
over aspects of their therapy, and manage their diabetes
with growing autonomy from healthcare professionals and
medical institutions. The resulting dose-adjustment for
normal eating course, with a 12-unit curriculum, covers
a range of issues: from understanding diabetes and the
way insulin works, to understanding food quality and its
interactions with insulin and managing on holiday (see Box).
In striking contrast to the DCCT,
improvements in HbA1c were not
associated with an increased
risk of severe hypoglycaemia.
During the early 1980s, the programme was based on intensified insulin therapy and ushered in the loosening of
previously rigid rules for nutrition and daily schedules. Over
the decades since then, the five-day programme has been
translated into general hospitals throughout Germany, and
has maintained its efficacy – significant reductions in HbA1c
values, ketoacidosis, hospitalizations and sick leave.2 This
success has been repeated in a number of other European
countries.3,4,5 In striking contrast to the Diabetes Control and
Complications Trial (DCCT), those improvements in HbA1c
values were at no time associated with an increased risk of
severe hypoglycaemia – quite the contrary: the incidence
was halved.
Implementing the German system
During the 1990s, the treatment and teaching programme
December 2011 • Volume 56 • Special Issue 2
for intensified insulin therapy was rolled out to nearly all
the specialist hospitals in Germany. The precondition for
successful implementation countrywide was the provision of
training for physicians, nurses and dietitians. To date, more
than 3,000 people, primarily nurses and dietitians, have undertaken the 12-week course to become a diabetes educator.
Over the years, about 200 departments of internal medicine
have agreed to implement continuous quality assurance
measures. These include re-examining a random sample of
patients 12 to 15 months after they have taken part in the
programme. Significant reductions have been seen in key
endpoints in a sample of 9,583 people with type 1 diabetes.6
They showed for the first time that the inverse association
between HbA1c and severe hypoglycaemia was not inevitable
during intensive insulin therapy. Before the intervention, the
incidence of severe hypoglycaemia was three times higher
in the lowest compared with the highest quartile of HbA1c,
whereas the risk was almost identical (but lower) across
HbA1c ranges during the year after the DTTP.
The programme was effective even in people with frequent
episodes of severe hypoglycaemia or ketoacidosis.6 Although
quality of life was not measured in the German programme,
there is good evidence from the British DAFNE study7 and
other trials that participants benefit psychologically from
enjoying dietary freedom. In a recent trial, there were strong
BOX: The 12-unit curriculum
P
athophysiology, insulin and injection
B
lood glucose self-monitoring, diet and
hypoglycaemia
B
asic diabetes information
R
educing insulin doses
I ncreasing insulin doses and ketoacidosis
P
hysical activity
H
bA1c, complications, smoking and follow-up
N
utrition training and carbohydrate counting
I nsulin pumps, contraception and pregnancy
T
ravelling and holidays
C
orrecting blood glucose
S
ocial issues
DiabetesVoice 17
MANAGEMENT, CARE AND PREVENTION
indicators that differences in the quality of diabetes care that
are caused by social inequalities disappear after treatment
and education.8
Ulrich Alfons Müller
Professor Müller leads the Working Group on Endocrinology and Metabolic
Diseases in the Department of Internal Medicine III at the University
Hospital Jena, Germany.
The Disease Management Programme
In 2004, the Disease Management Programme for Diabetes
was introduced into the German healthcare system, and
structured diabetes education was an integral part of the
Programme. As a result, people have the right to access
diabetes education. Remuneration for the education programmes is EUR 600 per person per course. In one of the
biggest German states, North Rhine-Westphalia, 18,441
people (65% of the of the type 1 diabetes population) registered in the Disease Management Programme in 2009.9
There is good evidence that
participants benefit psychologically
from enjoying dietary freedom.
Diabetes education – what we can learn!
There are some fundamental principles underpinning our
vision for structured education programmes for people with
long-term conditions like type 1 diabetes – or indeed type 2
diabetes. These should allow the healthcare professional to
help the patient to identify his or her personal problems and
issues with diabetes or hypertension, and their treatment.
We must keep in mind that it is the ‘empowered’ patient who
defines his or her own treatment goals and takes decisions
relating to the treatment of diabetes or hypertension; our
role as healthcare professionals is to inform and facilitate
(provide the necessary tools).
The principles we developed in the type 1 diabetes programme can be adopted to deliver specific strategies for
people with type 2 diabetes – and within that group, for
those who are on insulin and those who are not. Physicians
and nurses and other healthcare professionals need training
to deliver the programmes.
Our role as healthcare
professionals is to inform and
provide the necessary tools.
Increasingly, computer programs and sophisticated technical
devices are offered to manage diabetes. But we should all
be aware that while the use of electronic records facilitates
evaluation of the programme, those technologies could
never replace a fully trained diabetes educator.
18
DiabetesVoice
References
1 S tolte K, Wolff J. Die Behandlung der kindlichen Zuckerkrankheit bei
frei gewählter Kost. Ergebn Inn Med Kinderheilk 1939; 56: 154-93.
2 J örgens V, Grüßer M, Bott U, et al. Effective and safe
translation of intensified insulin therapy to general internal
medicine departments. Diabetologia 1993; 36: 99-105.
3 S tarostina EG, Antsiferov M, Galstyan GR, et al. Effectiveness and costbenefit analysis of intensive treatment and teaching programmes for
Type 1 (insulin dependent) diabetes mellitus in Moscow - blood glucose
versus urine glucose self-monitoring. Diabetologia 1994; 37: 170-6.
4 P
ieber TR, Schattenberg S, Brunner A, et al. Evaluation of a
structured outpatient group education programm for intensive
insulin therapy. Diabetes Care 1995; 18: 625-30.
5 D
AFNE Study Group. Training in flexible, intensive insulin management to
enable dietary freedom in people with type 1 diabetes: dose adjustment for
normal eating (DAFNE) randomised controlled trial. BMJ 2002; 325: 746.
6 S ämann A, Mühlhauser I, Bender R, et al. Glycaemic control and
severe hypoglycaemia following training in flexible, intensive insulin
therapy to enable dietary freedom in people with type 1 diabetes: a
prospective implementation study. Diabetologia 2005; 48: 1965-70.
7 S peight J, Amiel SA, Bradley C, et al. Long-term biomedical and psychosocial
outcomes following DAFNE (Dose Adjustment For Normal Eating) structured
education to promote intensive insulin therapy in adults with sub-optimally
controlled Type 1 diabetes. Diabetes Res Clin Pract 2010; 89: 22-9.
8 B
äz L, Müller N, Beluchin E, et al. Differences in the quality of diabetes care
caused by social inequalities disappear after treatment and education in a
tertiary care centre. Diabet Med 2011. doi: 10.1111/j.1464-5491.2011.03455.x
9 H
agen B, Altenhofen L, Blaschy S, et al. Qualitätssicherungsbericht 2008
Disease-Management-Programme in Nordrhein
www.kvno.de/downloads/qualbe_dmp08.pdf
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
Taking the benefits
of DAFNE to the
UK and beyond
Stephanie A Amiel, Julia Lawton, Simon Heller
Two English diabetologists were among an international audience while
Michael Berger told it to throw away the diet from the therapeutic approach
to type 1 diabetes. That caught their attention. Berger was describing was
a treatment programme that improved diabetes control in real terms.
In contrast to the Diabetes Control and Complications Trial (DCCT),
then still running, this was a programme that delivered lower average
blood glucose concentrations and HbA1c and reduced the risk of severe
hypoglycaemia. The DCCT seemed to show that this was not possible: the
lower the HbA1c, the lower the risk of vascular complications but with a
much higher risk of hypoglycaemia. Just over a year later, teams from
King’s College Hospital London, Sheffield University and North Tyneside
Hospital, all in the UK, visited Dusseldorf, Germany, to find out what
Professor Berger’s team was doing.
As Ulrich Müller has described in the
previous article, education underpinned
the Dusseldorf approach. The UK
teams observed a five-day programme
of structured education in flexible insulin therapy, which aimed to transfer
the healthcare professionals’ knowledge
and skills in insulin therapy to the insulin user. Greatly impressed, and with
December 2011 • Volume 56 • Special Issue 2
the support of the German team, we
brought their Treatment and Teaching
Programme for Flexible Insulin Therapy
to the UK.
Taking DAFNE to England
It took a grant from the charity Diabetes
UK and more than a year of hard work
to set up the Dose Adjustment for
Normal Eating (DAFNE) programme
in England. A group of dietitians, specialist nurses and doctors translated
the German teaching aids and received
training in the principles of the programme and in the art and science of
delivering education to adults. There
were some challenges and we had to
abandon some long-held beliefs of our
own: dietitians were concerned about
reducing the emphasis on healthy eating; doctors worried about abandoning
the prescription of regular food intake
and the classic meal-snack-meal-snack
pattern we believed was necessary to
minimize hypoglycaemia risk, and the
need to inject soluble (regular) insulin 30 minutes before eating in doses
decided by the doctor. But we made a
decision early on that we should follow
the evidence: the German programme
worked and we should not change it.
Compared to the German diet, the UK
diet is much higher in carbohydrates, so
we needed to revise the DAFNE food
DiabetesVoice 19
MANAGEMENT, CARE AND PREVENTION
models and images. Professor Berger’s
team supported us throughout and observed our first course.
UK findings added to
evidence from across
Europe and Latin
America to show that
DAFNE is effective.
The rest is history. The Diabetes UKfunded trial of DAFNE demonstrated
clinically relevant reductions in HbA1c
at both six months and one year after
courses, with other improvements in
cardiovascular risk and no rise in severe hypoglycaemia.1 These findings
contributed to the growing evidence
base from Germany and other countries
and regions, including Austria, Latin
America and Eastern Europe, to show
that the programme is effective. The
improvements in diabetes control were
found to be cost-effective.2 Importantly,
DAFNE was the first programme to
measure improvements in quality of life.
The UK Department of Health funded
the implementation of DAFNE to over
70 diabetes centres in England, while
many more UK centres deliver variants
on the Assal-Berger curriculum.
In the UK, DAFNE is unique in having a health care professional training
programme, a published evidence base
for its efficacy, a peer-review system to
ensure quality of teaching, a nationwide audit programme and a quality
assurance programme to maintain the
consistency of teaching. An annual
meeting of educators and doctors from
all the UK centres (and often visitors
from elsewhere) reviews progress and
considers new research. The curriculum
evolves but we try only to modify the
programme in ways that either already
have an evidence base or that we can
20
DiabetesVoice
red
Essential components of a structu
7
education programme
P
erson-centred philosophy
A
structured curriculum
T
rained educators
A
quality assurance programme
A
udited outcomes
audit in order to ensure that any changes
result only in improvements.
There are problems of course. Old habits die hard, and constant vigilance is
required to ensure that all DAFNE
courses remain true to the DAFNE
principles. Newer insulins offer potential benefits but we do not yet have the
data on how best to incorporate them
into the DAFNE regimens. We made
some obvious mistakes that, with hindsight, were rather obvious – the absence
of a continuing education programme
for the graduates of the DAFNE courses
being a very obvious one that we are
now addressing.
The group approach
enhances learning,
helps to overcome
feelings of isolation
and enables people
to compare their
experiences.
Keys to success
We do not know precisely what it is
about the DAFNE-type programmes
that deliver benefit. As Ebaa Alozairi
points out in her article, the key lies
in bringing people with type 1 diabetes together to meet, learn and share
experiences. This impression has been
reinforced by research being undertaken in the UK, funded by the National
Institute of Health Research (NIHR).
The researchers found that the group
approach enhances learning, helps to
overcome feelings of isolation and enables people to compare their experiences
of applying DAFNE principles, supporting more nervous people to ‘take the
leap’ or making dose adjustments that
have worked for others.3 Support from
empathic educators, avoiding direct instruction but referring to DAFNE rules,
is also important.
Meanwhile, the DAFNE insulin regimen, which is by no means unique,
gets as close to physiology as possible
with conventional insulins: twice-daily
injections of low-dose intermediateacting insulins to provide the basal insulin that controls endogenous glucose
production; pre-meal doses of fastacting insulin that are adjusted every
meal to match carbohydrate content
– modified if indicated by a pre-meal
blood test – injected before eating; and
algorithms for dose adjustment that
start with known physiology and are
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
adjusted in predictable ways for each
user, based on his or her own responses
in pre-meal and pre-bed blood testing.
We do know that both users and educators find value in the way the course
includes and also extends beyond improved biomedical outcomes. DAFNE
aims to put the person with diabetes in
control and it appears to achieve this
for most users. Maintaining the quality of the courses as the programme
expands requires effort and resources
– in terms of time and people as well
as money. For users, sustaining in the
long term the benefits derived from
DAFNE courses can be a challenge and
much effort is going in to understanding how we can support them to make
this happen.
The course graduates are the main movers in this: UK DAFNE graduates have
created their own website and developed
an application to support carbohydrate
counting, which has been made freely
available. The UK programme has provided training to healthcare professionals
in other countries. It has developed a
model in which larger centres can support smaller ones to obtain DAFNE with
the engagement of all the professional
teams involved.4 Meanwhile, the NIHR
programme, which is being coordinated
in Sheffield (UK), is exploring alternative forms of course delivery and ways
of helping course graduates to sustain or
improve on their outcomes. One area to
research is why some of the biomedical
outcomes of the programme are less well
sustained than the psychological and
quality-of-life benefits5 and why biomedical outcomes vary between countries.
Making DAFNE work worldwide
Most importantly, the research programme is listening to what people
with diabetes have to say. To date, we
have found that most people were glad
to have been able to 'do DAFNE', and
remain keen on and committed to sustaining its approach. There is clear demand for ongoing support from health
professionals who are trained in an
approach that is responsive to people’s
personal circumstances – suggesting
that one-to-one, rather than group,
follow-up, and being able to ask for
help as and when needed, may be most
appreciated.6 A national database is
being maintained also, which collects
information not just to ensure that the
programmes are delivering benefit but
also to facilitate research into which
approaches and strategies are effective
and which are not.
That ongoing research and a growing
number of committed and enthusiastic
healthcare professionals and people with
type 1 diabetes are working to establish,
extend and improve DAFNE’s diabetes
education web. Their endeavour needs
resources and support but, as these
pages hope to show, DAFNE is already
flourishing internationally.
UK DAFNE graduates have
created their own website and
developed an application to
support carbohydrate counting.
December 2011 • Volume 56 • Special Issue 2
Stephanie A Amiel, Julia
Lawton, Simon Heller
Stephanie A Amiel is the RD Lawrence Professor
of Diabetic Medicine at King's College London,
UK. Professor Amiel is Editor-in-Chief of
Diabetes Voice and was chair of the DAFNE
UK Executive Committee from 2001 to 2011.
Julia Lawton is a Senior Research Fellow in the
Public Health Sciences section of the Centre for
Population Health Sciences at the Medical School
of the University of Edinburgh, Scotland.
Simon Heller is Professor of Clinical
Diabetes at Sheffield University (UK) and
Chief Investigator of the National Institute
of Health Research Programme, ‘Improving
management of Type 1 diabetes in the UK: the
DAFNE programme as a research test-bed’.
References
1 D
AFNE Study Group. Training in flexible,
intensive insulin management to enable
dietary freedom in people with type 1 diabetes:
dose adjustment for normal eating (DAFNE)
randomised controlled trial. BMJ 2002; 325: 746.
2 S hearer A, Bagust A, Sanderson D, et al.
Cost-effectiveness of flexible intensive
insulin management to enable dietary
freedom in people with Type 1 diabetes in
the UK. Diabet Med 2004; 21: 460-7.
3 L
awton J, Rankin D. How do structured
education programmes work? An ethnographic
investigation of the dose adjustment for normal
eating (DAFNE) programme for type 1 diabetes
patients in the UK. Soc Sci Med 2010; 71: 486-93.
4 R
ogers H, Turner E, Thompson G, et al. Huband-spoke model for a 5-day structured patient
education programme for people with Type 1
diabetes. Diabet Med 2009; 26: 915-20.
5 T
he DAFNE Study Group (2010). Long-term
biomedical and psychosocial outcomes following
DAFNE (Dose Adjustment For Normal Eating)
structured education to promote intensive insulin
therapy in adults with sub-optimally controlled
Type 1 diabetes. Diab Res Clin Pract 2010; 89: 22-9.
6 R
ankin D, Cooke DD, Clark M, et al; UK
NIHR DAFNE Study Group. How and why
do patients with Type 1 diabetes sustain their
use of flexible intensive insulin therapy? A
qualitative longitudinal investigation of patients'
self-management practices following attendance
at a Dose Adjustment for Normal Eating
(DAFNE) course. Diabet Med 2011; 28: 532-8.
7 D
iabetes UK, UK Department of Health,
UK National Diabetes Support Team. How
to Assess Structured Diabetes Education: An
improvement toolkit for commissioners and local
diabetes communities. www.diabetes.org.uk/
Professionals/Publications-reports-and-resources/
Reports-statistics-and-case-studies/Reports/
Structured-Education-Self-Assessment-Toolkit/
DiabetesVoice 21
MANAGEMENT, CARE AND PREVENTION
Positive results in
Australia – OzDAFNE
takes up the challenge
Dianne Harvey
Australian diabetes healthcare
professionals in Melbourne
learned about the DAFNE
programme for people with type 1
diabetes in 2004, during a visit
to the International Diabetes
Institute there by Stephanie
Amiel. Rather like the UK teams
a few years earlier, a team
of nine health professionals
from four Australian centres
undertook DAFNE training in the
UK that year. Prior to this, there
were no evidence-based group
programmes providing structured
education for people with type 1
in Australia. After the training
period, the Australians returned
home and ran their first courses:
in early 2005, OzDAFNE was born.
22
DiabetesVoice
OzDAFNE has grown since its modest early stages, from the four original OzDAFNE centres to 20 centres
countrywide, and the programme has
provided training for centres in New
Zealand and Singapore. An OzDAFNE
collaborative was formed to link all
Australian centres, provide governance
for DAFNE at the national level and
maintain links with UK DAFNE. The
national coordinating centre, Diabetes
Australia-Victoria, is partnered with
Mater Health Services in Brisbane to
oversee the training and peer review of
new and existing centres, and contribute
to research.
One of the first and most important
challenges in introducing DAFNE to
an Australian audience was the development of ‘Australianized’ resources.
Changes to the curriculum and handbook were minor but included, for example, regulatory guidelines around
driving. The carbohydrate counting
booklet was modified to allow for typical Australian foods and snacks, and the
carbohydrate values were sourced from
an Australian database. Finally, we replaced the UK DAFNE ‘Jaffa cake’ (buscuit) logo with a picture of a traditional
Australian sweet – the Lamington.
OzDAFNE has been
integrated into
community health
centres, private
practice and Diabetes
Australia associations.
With modifications to the resources
complete, our focus shifted towards
increasing the number of OzDAFNE
centres in order to provide better access to courses for people with type 1
diabetes around the country. In the
UK, DAFNE is normally run by hospitals in a clinical setting. However,
major hospitals in Australia have struggled to incorporate DAFNE into their
busy clinical environments within
limited budgets. Although some hospital clinics have managed to do so,
the OzDAFNE programme has also
been integrated into a variety of other
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
healthcare settings, such as community health centres, private practices
and Diabetes Australia associations.
As these non-clinical settings lack
direct access to general practitioners
and endocrinologists, a formal doctor’s
consent process, including an insulin
order form, was devised to allow the
OzDAFNE educators to function.
Different strokes…
We also needed a different model for
quality assurance. Australia is a vast
country, so attempting to implement
the UK DAFNE model of external
peer review without adequate funding
to support the travel and accommodation required was problematic. As
a result, a modified quality assurance
programme has been implemented that
is based mainly on internal peer review,
with external checks and administration
carried out by the national coordinating centre. We are currently working
towards a model in which there is a lead
OzDAFNE centre in every state that
takes responsibility for state training
and quality assurance measures.
The absence of dedicated funding for
OzDAFNE affects our quality assurance
programme and impacts on the adoption of OzDAFNE by new centres – as
well as ongoing provision of DAFNE
courses in existing centres. Currently,
individual OzDAFNE centres self-fund
their services through a variety of ad hoc
methods and activities and participant
contributions. For example, a number of
community health centres have secured
funding for OzDAFNE through chronic
disease and self-management funding
programmes; and one private practice
model relies on pharmaceutical industry support. The National Diabetes and
Supply Scheme provides the majority
of funds to Diabetes Australia-Victoria
as the coordinating centre. This con-
December 2011 • Volume 56 • Special Issue 2
tributes towards national
ministration, training and
quality assurance costs.
Ongoing dedicated funding is needed to maintain
finance for the OzDAFNE
programme at the national
level, and to assist individual centres to sustain it.
Rebates from private health
insurance companies are being investigated as a potential
source of funding.
ad-
Educators often
comment that the
DAFNE training was
the best professional
development they have
ever experienced.
… producing similar benefits
Despite the particular challenges involved in bringing DAFNE to Australia,
the OzDAFNE outcomes are quite similar to those shown in Germany and the
UK. An audit of OzDAFNE data on clinical outcomes included 145 people (preDAFNE and 12 months post-DAFNE)
with type 1 diabetes who participated in
courses at seven Australian diabetes centres between February 2005 and March
2007. A year after taking part in DAFNE,
our participants had better blood glucose
control (average HbA1c fell from 8.2%
to 7.8%), reduced incidence of severe
hypoglycaemia, slightly reduced weight
(average weight dropped from 75.1 kg to
74.2 kg) and reduced anxiety, depression
and diabetes-related distress.1
OzDAFNE educators report enthusiasm
for the DAFNE programme and often
comment that the DAFNE training was
the best professional development they
have ever experienced. This enthusiasm was evident in June 2011, when
75% of DAFNE educators from all over
Australia and New Zealand attended
our inaugural OzDAFNE professional
development day in Melbourne.
Despite the many challenges involved
in implementation in Australia, the
outcomes of the course participants
described above speak volumes for
DAFNE’s efficacy and the potential
benefits of its expansion. Those positive
results and the passion of the OzDAFNE
educators support the maintenance of
the courses and the implementation of
the programme throughout Australia.
Dianne Harvey
Dianne Harvey is dietitian and
OzDAFNE coordinator, Australia.
References
1 M
cIntyre HD, Knight BA, Harvey DM,
et al. Dose adjustment for normal eating
(DAFNE) – an audit of outcomes in
Australia. MJA 2010; 11: 637-40.
DiabetesVoice 23
MANAGEMENT, CARE AND PREVENTION
Never say never –
implementing DAFNE
in Kuwait
Ebaa Alozairi
There is overwhelming evidence that
improving HbA1c reduces the risk of longterm complications and improves quality
of life. In Kuwait, however, few people with
diabetes reach their target levels and, as
a consequence, remain at risk of diabetes
complications. Healthcare professionals ask
the people in their care to test their blood
glucose three or four times a day. Yet in
many regions, very few people with diabetes
have received education on how to adjust
their insulin according to their blood glucose
results. Unless appropriate education and
skills training are provided, blood glucose
outcomes will not be affected – however
much encouragement is offered. Ebaa
Alozairi describes successful efforts to bring
to Kuwait an educational and therapeutic
approach based on dose adjustment, the
recent achievements and current progress
of DAFNE trainers and graduates, and plans
for expansion throughout the Middle East.
24
DiabetesVoice
There is lack of diabetes educators and dietitians in Kuwait,
and resources vary according to geography. Some diabetes
teams offer a substantial amount of education but this is
delivered largely on a one-to-one basis and many hospitals
lack facilities. Many dietitians in Kuwait either follow the
North American methods – either an insulin-to-carbohydrate ratio of 1:15 or varying the ratio according to total
daily dose. Both of these present mathematical challenges
to people with diabetes, who often need to use a calculator
to work out the correct dose.
While I was in the UK receiving clinical diabetes and endocrine training a few years ago, I travelled to the Joslin
Diabetes Center, Boston, USA, with a Fulbright grant. The
Joslin offered an impressive variety of high-quality courses
for people with diabetes. I observed many people who had
travelled long distances across borders to attend sessions.
Strikingly though, none of the courses had undergone randomized controlled trials or had external quality assurance.
Back in the UK, I undertook training to become a DAFNE
doctor. I was impressed by that programme too: it seemed
highly practical – the use of 10 g rather than 15 g carbohydrate portions on which to base insulin, making it easier
for people with diabetes to do the necessary maths. Firmly
based on empowerment, the programme was methodologically sound, not unduly prescriptive and highly valued
by the participants. I went on to complete the quality assurance training offered by the UK programme. My idea
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
was to transfer the DAFNE model to Kuwait, where I was
convinced it would bring considerable benefits to people
with diabetes and the Ministry of Health.
Founded on empowerment,
DAFNE is methodologically sound,
not unduly prescriptive and
highly valued by participants.
Initially, I was concerned that the model might not work in
Kuwait mainly due to cultural differences: patient empowerment is not standard practice for Middle Eastern doctors
and people with diabetes in many cases prefer to depend on
their healthcare professional for guidance. The change from
a prescriptive approach to patient-centred care is difficult to
implement and can be confusing from the patient's perspective. The UK team agreed to support the pilot programme
us throughout its implementation in Kuwait.
In 2009, two dietitians from the Al Amiri hospital made
a structured observational visit to the UK and completed
DAFNE training. Back in Kuwait, the DAFNE materials were
translated into Arabic and adapted to Kuwaiti culture. With
support from the head of the diabetes unit at Al Amiri, we
were able to pilot DAFNE.
Initially, two courses were conducted for groups of women
and men separately; a third course was mixed gender. The first
sessions were held in the morning, like in the UK. However,
we encountered difficulties recruiting, as participants generally were not able to take time off from work. Moreover,
many people did not want to disclose their diabetes in the
workplace due to the strong sense of stigma related to having
the condition. So the sessions were moved to an afternoon
and evening timetable, which was welcomed by participants.
During the pilot study, all participants expressed their satisfaction – equipped, in many cases, for the first time, with the
skills they needed to manage their own diabetes. Many course
participants with type 2 diabetes, which is very prevalent in
Kuwait, were happy to meet others with less-common type 1
diabetes, which generated a positive discussion.
Never say never!
Having completed our pilot, the team presented preliminary
findings and a plan to extend DAFNE nationwide to the
Kuwait Diabetes Society. Despite our positive results, some
senior members objected to the idea of group education.
They regarded people in Kuwait as very discreet and would
be unwilling to discuss their diabetes in a group. So despite
our findings, the model was not altogether welcomed. Also,
some professionals were not happy that DAFNE educators were adjusting insulin dosages instead of the relevant
physician. However, the positive experiences of people with
diabetes engaged in DAFNE and our never-say-die attitude
drove the educators on to continue delivering DAFNE –
albeit in only one hospital.
Participants expressed their
satisfaction – equipped for
the first time with the skills
they needed to manage
their own diabetes.
December 2011 • Volume 56 • Special Issue 2
DiabetesVoice 25
MANAGEMENT, CARE AND PREVENTION
Having successfully presented our findings to the newly appointed Director General of the Dasman Diabetes
Institute, the DAFNE programme was recognized as the
national course for type 1 diabetes. To be held at the Dasman
Institute, it the course is open to people from all regions of
the country. All people with type 1 diabetes are welcomed
to register and the referral is open to all doctors living and
working in Kuwait.
The DAFNE project was launched at the Dasman Institute
in November 2010. The structured teaching programme is
delivered to groups of between six and eight participants under the supervision of DAFNE-trained educators. Healthcare
professionals are invited to attend as observers but with a
maximum of two per course. Most of the training is built
around group work, sharing and comparing experiences with
other participants. However, there are opportunities for each
person to speak to DAFNE educators individually. Acceptance
has been remarkably good; a number of DAFNE graduates
have requested that the course be extended to two weeks!
To date, eight courses have been completed in 10 months. A
special one-day Ramadan course recently gave participants
the opportunity to practise estimating the carbohydrate
content of particular complex foods that are eaten mainly
during Ramadan.
The DAFNE Kuwait collaborative has established strong
links with the UK, keeping the UK DAFNE group informed
at all stages, to ensure consistent standards of delivery.
With supports from UK DAFNE and the Dasman Diabetes
Institute, Kuwait has been made the training centre for the
Middle East region. We are delighted to provide training to
any centre wishing to adopt this very effective programme.
Acceptance has been remarkably
good; a number of DAFNE graduates
have requested that the course
be extended to two weeks!
Positive outcomes
To date, 45 people with diabetes have completed the DAFNE
course. None have required admission to hospital because
of their blood glucose. There has been a marked reduction
in rates of hypoglycaemia; most people are requiring fewer
visits to the healthcare professionals and consuming less
than half of their pre-course insulin dosages. Many have
26
DiabetesVoice
improved HbA1c. Most strikingly, some graduates want
refresher courses, proposing that they be able to follow
their HbA1c as a group.
DAFNE is now part of the compulsory training for doctors
during the Diabetes and Endocrinology degree programme
in Kuwait.
What do DAFNE graduates say?
It is encouraging to read the universally positive feedback from people who have completed a DAFNE course
in Kuwait. A few of the graduates, without any prompting,
wrote an article in English and Arabic, which was published
in a number of newspapers, describing their very positive experience. Another participant paid for all course members to
dine together and refused offers of payment from his peers,
saying that he was “relatively new to my diabetes journey
and for the first time I feel normal”. The positive feedback
here is stronger even that that I had observed in UK.
Future plans
Currently, all the various psychological questionnaires and
biochemical data (weight, hypoglycaemic events, HbA1C)
are collected both at baseline and at follow-up, and crosscultural differences will be examined. A Ramadan-specific
trial will be carried out next year. People with type 1 diabetes and healthcare professionals from the Middle East
are welcomed to attend DAFNE Kuwait to observe the
positive impacts.
Ebaa Alozairi
Ebaa Alozairi is Assistant Professor at Kuwait University,
nutrition specialist on the American Board of Physician,
a consultant in Diabetes and Endocrinology and lead
DAFNE clinician in Kuwait ([email protected]).
Acknowledgments
The author would like to thank Simon Heller and DAFNE
UK, the Kuwait DAFNE educators, the Dasman Diabetes
Institute, the Head of the Diabetes Unit at Al Amiri Hospital,
DAFNE graduates and healthcare professionals in Kuwait.
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
Great results for
DAFNE Singapore –
next stop,
South-East Asia
Su-Yen Goh and Daphne Gardner
In November 2010, a pioneering team comprising
a nurse educator, a dietitian and an endocrinologist from Singapore General Hospital completed a
DAFNE course and postcourse educator training in
Australia, at the OzDAFNE
centre, Diabetes AustraliaVictoria. This was the first
step in a process that successfully took the DAFNE
model Singapore. The
Clinical Leads for the Singapore initiative describe
the experience so far and
look to the future and continental development of
their growing programme.
December 2011 • Volume 56 • Special Issue 2
Upon returning to Singapore, the newly
christened SgDAFNE team adapted the
materials shared by OzDAFNE and developed a culturally relevant SgDAFNE
programme, including a modified carbohydrate portion booklet for use in
Singapore and the rest of South-East
Asia. To the best of our knowledge,
ours is the first centre in Asia to offer DAFNE, and we are growing and
developing. With two courses given in
2011, and at least three more scheduled
for 2012, we also provide healthcare
professional DAFNE awareness events/
sessions, such as on World Diabetes
Day this year.
The inaugural course for SgDAFNE
in April 2011 was conducted under
the watchful eye of an auditor from
Diabetes Australia, and OzDAFNE
have included us in the OzDAFNE
collaborative. We are committed to
contributing to the OzDAFNE database until such time as the SgDAFNE
programme is able to establish its own
independent collaborative.
DAFNE was a paradigm
shift for people who
were not attuned
to the concept of
empowerment.
Many challenges have surfaced during
the development and implementation of
SgDAFNE. Prior to DAFNE, there were
no structured or standardized education
and self-management programmes for
people with type 1 diabetes in Singapore.
This was a paradigm shift for most
people, some of whom functioned in
a rather paternalistic and hierarchical
doctor-patient relationship and were
not attuned to the concept of empowerment. The programme demands a
higher intensity of self-monitoring of
blood glucose compared with routine
care; purchases of glucometer and test
DiabetesVoice 27
MANAGEMENT, CARE AND PREVENTION
strips are out-of-pocket expenses with
no insurance reimbursement or government healthcare financing available.
Some people previously had never done
blood ketone testing, as the cost is prohibitive – up to USD 4 per test strip.
The very act of
injecting insulin in
public was a daunting
barrier for some.
Another major task was developing the carbohydrate counting material for the local context. The dietetics
team laboured long and hard, and were
thrilled to produce our own SgDAFNE
carbohydrate portion booklet in the first
quarter of 2011. In adapting the diabetes education material, we had to take
into consideration the socio-cultural
contexts of food and diabetes: many
Singaporeans dine out for most meals of
the day, and it was often challenging to
calculate hidden carbohydrates (such as
28
DiabetesVoice
in sauces and gravies) or estimate accurately portion sizes. Many Singaporeans
tend to be ‘grazers’, snacking throughout
the day rather than eating a full meal at
regular times.
Although the DAFNE curriculum
equips people with the ability to calculate and dose for snacks, difficulties
arose in terms of interpreting pre-meal
glucose concentrations and insulin
stacking. The very act of injecting insulin in public, as well as weighing foods,
was a daunting barrier for some.
To the delight of
all involved, some
people have had dose
reductions of between
25% and 40%.
With two groups of graduates, the
SgDAFNE team has also found that
the local people may be more insulin
sensitive (requiring 1:1 rather than 1.5:1
or 2:1 ratios) than previously thought.
The issue of over-insulinization before
entering the programme has also surfaced; to the delight of participants and
the SgDAFNE team alike, some people
have had dose reductions of between
25% and 40%.
SgDAFNE has been an exciting journey
for all involved and we look forward to
extending the programme island-wide
and throughout South-East Asia.
Su-Yen Goh and Daphne Gardner
Su-Yen Goh and Daphne Gardner
are the Clinical Leads for SgDAFNE
at Singapore General Hospital.
Acknowledgement
SgDAFNE was supported by an
unrestricted educational grant from
sanofi-aventis Singapore with additional
support from Abbott Diagnostics.
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
Making progress with
immune therapies
for type 1 diabetes
Mark Peakman
Thirty-five years on from the
demonstration that type 1 diabetes
has an autoimmune basis, we have
learned an enormous amount
about the disease. We know its
genetic basis (immune genes),
its pathological basis (immune
cells) and we would expect to
be converting this insight into
therapeutic advances (immunebased). Certainly, the field of
immunotherapy for type 1 diabetes
is very active. Here, Mark Peakman
reviews the progress being made
and scans the horizon for the most
likely future breakthroughs.
December 2011 • Volume 56 • Special Issue 2
In the mid-1970s, autoantibodies that
bind to targets in cells in the islets of
Langerhans were described in the scientific literature. They have since become
established as a major biomarker for
type 1 diabetes, both at diagnosis and
in the preclinical prodrome. We have
since learned that the disease results
from autoimmune destruction of the
insulin-secreting beta cells in the islets, a process involving the T and B
lymphocytes and dendritic cells of the
immune system (Figure).
Focusing on the beta cells
The disease arises on a distinctive genetic background, in which variants of
genes that regulate immune responses
are the predominant feature. This understanding, allied with a range of therapeutics (many arising from the field of
transplantation), a better understanding of how immunological tolerance is
maintained and lost, and several animal
models in which new therapies can be
tested, has led to a period of intense
activity as these advances are translated.
Clinical trial consortia, such as Type 1
Diabetes TrialNet and the Immune
Tolerance Network, linking centres with
expertise in the field to do collaborative
research, have been pivotal in promoting the acceptance of study designs that
focus on, and are adequately powered
to detect, the preservation of beta-cell
function (measured as the C-peptide
response to a challenge) in new-onset
type 1 diabetes, typically measured at
six, 12 and 24 months after the introduction of the novel therapy.
Stimulated C peptide has proved an acceptable surrogate for any beneficial effects of therapy in preserving remaining
beta cells, which would be expected to
have an impact on glycaemic control if
sufficient endogenous insulin production
remains. A further emerging principle
DiabetesVoice 29
MANAGEMENT, CARE AND PREVENTION
cytokines
Th
B
α
3. Via blood
β cells
TREG
CTL
CTL
1. Islet
DC
Th
B
DC
2. Pancreatic
lymph node
(shown in white)
the pancreatic islet express proteins
The insulin-secreting beta cells of
B and cytotoxic
(shown in pink) and activate T and
that are picked up by dendritic cells
cytokines as
) to destroy the beta cells, releasing
lymphocytes (green, yellow and blue
in black can damp down the process.
they do. Regulatory T cells shown
is that trials are more likely to be able to
show benefit if studies are started soon
after diagnosis; 100 days from initial
presentation to the first administration
of the study drug is now the norm.
What kind of therapeutic strategies
are emerging?
There are currently two main competing solutions being developed which
target components of the immune system. The first is immune modulation via
such strategies as biologics that target T
lymphocytes, B lymphocytes, co-stimulatory molecules and cytokine pathways,
among others (see Figure). This is ‘nonspecific immunotherapy’ is designed
to act systemically, making no attempt
to target only the minority of T lymphocytes that cause beta-cell damage.
The lead compounds here have been two
monoclonal antibodies directed against
the CD3 protein on the surface of T
cells. Although it is not exactly clear how
anti-CD3 therapy works, two Phase II
30
DiabetesVoice
studies have indicated beneficial effects
on C-peptide decline.
Follow-up studies have even shown the
potential for a prolonged effect, with
preservation of C peptide for several
years in some people. Unfortunately,
the data emerging from subsequent
Phase III studies ending in 2011 were
mixed, although this may be attributable to the study design. Otelixizumab
(GlaxoSmithKline/Tolerx, Inc) was reported to have failed Phase III trials in
March 2011. The anti-CD3 antibody
Teplizumab, developed by Macrogenics
and Eli Lilly, also did not meet endpoints
in a Phase III trial in type 1 diabetes but
published data indicates that C peptide
was nonetheless preserved.
It is to be hoped that these drugs will undergo continued development to try and
identify optimal conditions for their use.
Another Phase II trial suggests that interfering in pathways of T-cell activation
with the drug Abatacept (an inhibitor
of T-cell co-stimulation) also can be
beneficial, and an earlier report had indicated that depletion of B lymphocytes
using Rituximab has clear, but transient
benefits. Thus, a small arsenal of agents
is being identified. Importantly, safety
and feasibility in the setting of newonset disease is becoming established,
along with the precedent of enrolling
adolescents and children into these
studies – important, as new-onset type 1
diabetes is common in this age group.
Antigen-specific immunotherapy
The second approach is termed antigenspecific immunotherapy (ASI). It is well
established that induction and restoration of immune tolerance is achieved
by administering the very target (autoantigen) against which the destructive
autoimmune response is directed. This
may seem counter-intuitive and likely
to ramp up the autoimmunity; but if the
autoantigen is given under appropriate
conditions, it seems to work, at least in
model systems.
There are different ASI strategies. Using
short antigenic peptides representing
sequences (epitopes) recognized by T
lymphocytes – known as peptide immunotherapy (PIT) – is in Phase I-III
development in clinical allergy and
Strategies for halting immune
damage to beta cells
Immune suppression with drugs
that inhibit T lymphocyte function
Immune modulation that promotes a better immune system
balance
Strategies to specifically promote
immune regulation in islets
Combinations of the above
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
other autoimmune diseases. PIT has
several advantages: highly efficient
target delivery; avoidance of antibody
development; relatively inexpensive synthesis costs; and the fact that the dose is
not limited by the biological effects of
the parent molecule. In Phase I studies
in our centre, it appears safe and well
tolerated. Future studies will be needed
to evaluate its full potential and the best
setting for its deployment.
Alternatively, whole proteins from the
beta cell have been used. The lead here
is insulin, given orally to first-degree
relatives without diabetes who already
have islet cell autoantibodies. A clinical
study conducted by TrialNet is based on
sub-study data that suggest that firstdegree relatives who have high titres
of anti-insulin autoantibodies might
expect particular benefit from this approach in terms of reduced progression
to clinical disease. Giving insulin by
mouth has no metabolic effect at the
dose used but takes advantage of the
natural immunological phenomenon
that ingested protein antigens are well
tolerated by the immune system. The
study will report in one or two years
and, it is hoped, will provide better understanding of the mechanisms of oral
immunological tolerance in humans.
The other advanced drug in the ASI
area was the whole beta-cell protein/
autoantigen GAD65 (glutamic acid decarboxylase isoform 65 kDa; Diamyd®
GAD65). Although promising results
(preservation of insulin reserve) were
reported in a post-hoc analysis of a subset of cases treated with GAD65-alum
prime and boost in 2008, a repeat conducted by TrialNet reported no benefit
in 2011. Full reporting of the results of
a Phase III study are expected, although
preliminary reports suggest no preservation of C-peptide preservation.
December 2011 • Volume 56 • Special Issue 2
What does the future hold for type 1
diabetes therapeutic strategies?
Can sense be made of these ebbs and
flows of positive and negative clinical
trial data? There is a picture emerging
that non-specific, biologic-based therapies are effective when given close to
diagnosis, whereas antigen-specific immunotherapy is not – probably because
it operates sub-optimally in such an active inflammatory setting. Encouraging
data from oral insulin studies suggest
that building tolerance against beta-cell
autoantigens may be useful if given early
and for prolonged periods. Moreover, its
excellent safety profile means that administration in at-risk groups is feasible.
Future developments for ASI will centre
on maximizing this potential, probably
using multiple antigens or better delivery
systems. New therapeutic modalities at
very early stages of evaluation include attempts to bolster immune regulation using the approach of adoptive cell transfer.
It seems probable that, like many complex human disorders of unknown aetiology, type 1 diabetes ultimately may be
controlled via a therapeutic approach that
combines multiple agents with different
modes of action. The advantages of such
a strategy include minimizing the toxicities and realizing the synergies that enhance and prolong efficacy. The degree to
which non-specific immunotherapy and
antigen-specific therapy are combined
may need to be different according to
the stage of disease, for lower risk in the
pre-diabetes setting and higher potency
in newly diagnosed people.
Mark Peakman
Mark Peakman is Professor of Clinical
Immunology at King's College
London, School of Medicine, UK..
Further reading
Staeva-Vieira T, Peakman M, von Herrath M.
Translational mini-review series on type 1 diabetes:
Immune-based therapeutic approaches for type 1
diabetes. Clin Exp Immunol 2007; 148: 17-31.
eakman M, von Herrath M. Antigen-specific
P
immunotherapy for type 1 diabetes: maximizing
the potential. Diabetes 2003; 59: 2087-93.
atthews JB, Staeva TP, Bernstein PL, et al.
M
Developing combination immunotherapies
for type 1 diabetes: recommendations
from the ITN-JDRF Type 1 Diabetes
Combination Therapy Assessment Group.
Clin Exp Immunol 2010; 160: 176-84.
www.diabetestrialnet.org
www.immunetolerance.org
www.jdrf.org
DiabetesVoice 31
MANAGEMENT, CARE AND PREVENTION
All that glitters is
why we need bet
trials and reporti
Rury R Holman
In an age of increasing global information overload, it is
becoming progressively more difficult to discern real health
and safety signals, or potentially beneficial possibilities, from
background noise. The explosion in exploratory analyses of
emerging large-scale medical record databases and registries
has helped to highlight many potential issues of interest. But
establishing the reality of such uncontrolled ‘findings’ can be
challenging. A major concern is that apparent associations,
which are identified by these often opportunistic analyses,
are frequently reported by the media and others as potential
‘medical breakthroughs’ or as possible ‘safety concerns’
for existing therapies. Remarkably, such reports often give
equal (or greater) prominence to unsubstantiated exploratory
findings than they do to robust results from properly
designed and conducted trials. As a result, these reports
can raise hopes or fears inappropriately in the population at
large. In addition, the almost daily publication of frequently
conflicting findings diminishes public faith in scientific
pronouncements and may preclude people taking note of
proven results that could be crucial to their future health.
32
DiabetesVoice
December 2011 • Volume 56 • Special Issue 2
MANAGEMENT, CARE AND PREVENTION
not gold –
ter
ng
An evidence-based approach to medicine has been adopted; it is recognized
that intuition, unsystematic clinical
experience and pathophysiological
rationale are insufficient grounds for
clinical decision making. Clinical observations can produce useful insights
but are hindered by small sample sizes
and the limitations in human processes
for making inferences. Observational
studies can provide compelling evidence
but inevitably are limited by the possibility that apparent differences are really
due to differences in patients’ prognoses
secondary to the post hoc selection of
treatment and control groups. One such
example was the observational finding
that women who took hormone replacement therapy appeared to have a reduced
risk of coronary heart disease. A randomized controlled trial (RCT), however, showed the reality: that hormone
replacement therapy increases rates of
thromboembolic events and gallbladder
disease.1 (The probable explanation is
that early adopters of hormone replacement therapy were more likely to have
been health-aware women with correspondingly healthier lifestyles.)
Randomization is
too important to
leave to chance.
RCTs provide the highest level of evidence and remain the gold standard,
although they are not always feasible: no
one has yet conducted a RCT for parachutes! All trials attempt to discover ‘the
truth’ but can only provide evidence of
the truth, not absolute proof. ‘The truth’
would be the answer to a research question arrived at by conducting a perfectly
executed study on everyone with the
characteristics of interest. Participants
in RCTs receive the interventions at random to help ensure similarity of characteristics both known and unknown
December 2011 • Volume 56 • Special Issue 2
DiabetesVoice 33
MANAGEMENT, CARE AND PREVENTION
– such as demographics, genetic make
up, lifestyle choices – at the start of the
comparison. Individuals, groups and
the order in which measurements are
obtained all can be randomized.
Randomization must be conducted in
such a way that the allocation of different interventions cannot be influenced
by participants or those conducting the
study – randomization is too important to leave to chance. Clinical trial
design and reporting has improved
immeasurably over time, especially
with the widespread adoption of the
CONSORT guidelines.2 RCTs seek to
establish whether different interventions
lead to different outcomes. However, in
order for a difference to be a difference,
it must make a difference! A numerical
difference may be statistically significant
but if the size of the effect is not clinically relevant, then it is of little import.
Since the truth is rarely absolute, many
decisions in medicine continue to be
made on the balance of probabilities
and epidemiological data. Observational
data can identify signals of potential
good or harm, but cannot assign causality. Meta-analyses, however well conducted, depend ultimately only on trials
and studies that have been performed.
If the appropriate trials have not been
conducted, or indeed have not been
reported, then the conclusions will be
flawed. Fortunately, procedures for undertaking meta-analyses and systematic
reviews have become much more robust,
particularly with the aid of the Cochrane
Collaboration,3 among others.
Clearly, a more systematic approach is
needed when assessing rapidly evolving data from a myriad of sources that
have highly variable provenance. One
such example is the Mini-Sentinel pilot,4
which is giving the US Food and Drink
34
DiabetesVoice
Adminsitration (FDA) the opportunity
to develop the data infrastructure and
scientific tools needed to conduct active
safety surveillance of medical products
within a distributed system of large private and public healthcare databases.
Equally, trials are moving into a new
era, particularly in diabetes. The FDA
has issued industry guidance for the
evaluation of cardiovascular risk in
new therapies to treat type 2 diabetes.5
This requires that as they are assessed
for possible licensing, new agents be
studied in such a way as to ensure that
their potential to increase cardiovascular risk does not exceed stipulated
thresholds. This cardiovascular safety
requirement, which has added greatly
to the development costs of new drugs,
has also led to a rapid increase in the
number of cardiovascular outcome
trials being performed, with some
14 studies currently recruiting over
110,000 participants. These large-scale,
simple, mostly double-blind trials
comparing new agents with placebo,
will increase substantially the amount
of clinically relevant information for
treating type 2 diabetes.
The research community
has a duty of care to
report trials, studies
and ‘incidental’
findings in context.
However, smarter trials are needed.
Testing multiple interventions in factorial or head-to-head designs would
be more efficient, more informative
and more cost-effective. While trials
are likely to be powered based on the
time to the first primary endpoint,
subsequent events also should be captured routinely and evaluated in detail
to maximize our understanding of the
full impact of treatments – with respect
to both benefits and risks.
The research community has a duty of
care to report trials, studies and ‘incidental’ findings in context. In particular, a
more rigorous approach for reporting
observational findings is needed. In order
to help provide guidance for the media
and others when publicizing results from
exploratory studies, systematic reviews,
meta-analyses and RCTs, journals should
consider adding an evidence level rating
to relevant publications. Press releases
issued by investigators, sponsors, funding bodies and journals could do much
more to ensure a correct perspective is
given to media coverage. Ultimately,
routine sharing of individual-level data
from completed trials will help to decide
what it is that glitters and identify any
hidden nuggets, as has been done successfully with the Cholesterol Treatment
Trialists Collaboration and similar collaborative efforts.
Rury R Holman
Rury R Holman is the Director of the
University of Oxford Diabetes Trials
Unit, Honorary Consultant Physician
and a Senior Investigator at the UK
National Institute for Health Research.
References
1 H
ulley S, Grady D, Bush T, et al for
the Heart and Estrogen/progestin
Replacement Study (HERS) Research
Group. JAMA 1998; 280: 605-13.
2 A
ltman DG, Schulz KF, Moher D,
et al for the CONSORT Group.
The Revised CONSORT Statement
for Reporting Randomized Trials:
Explanation and Elaboration. Ann
Intern Med 2001; 134: 663-94.
3 w
w.cochrane.org
4 w
ww.mini-sentinel.org
5 w
w.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatory
Information/Guidances/UCM071627.pdf
December 2011 • Volume 56 • Special Issue 2
ADVERTISEMENT
ADVERTISEMENT
LANTUS ® Abbreviated Prescribing Information. 1. NAME AND PRESENTATION: Lantus 100 U/ml, solution for injection of insulin glargine is available in a vial of 5 & 10 ml,
cartridge of 3 ml for the following reusable pens only: Optipen, ClikSTAR Autopen 24 or Tactipen, cartridge of 3 ml for Opticlik, and prefilled disposable pens of 3 ml for Lantus
Optiset & Lantus Solostar. 2. THERAPEUTIC INDICATIONS: Treatment of adults, adolescents and children of 6 years or above with diabetes mellitus, where treatment with
insulin is required. 3. POSOLOGY AND METHOD OF ADMINISTRATION: Lantus should be administered once daily at any time but at the same time each day. The dosage
and timing of dose of Lantus should be individually adjusted. In patients with type 2 diabetes mellitus, Lantus can also be given together with orally active antidiabetic agents.
In children older than 6 years Lantus should be given in the evening. In children below the age of 6 years, Lantus should only be used under careful medical supervision. When
changing from a treatment regimen with an intermediate or long-acting insulin to a regimen with Lantus, a change of the dose of the basal insulin may be required and the
concomitant antidiabetic treatment may need to be adjusted. Close metabolic monitoring is recommended. Administration: Lantus is administered subcutaneously, should not
be administered intravenously and must not be mixed with any other insulin or diluted. For administration details see full SmPC. Patients must be educated to use proper injection
techniques and insulin label must always be checked before each injection to avoid medication errors between Lantus and other insulins. Renal impairment & hepatic impairment:
insulin requirements may be reduced. Elderly: deterioration of renal function may lead to a decrease in insulin requirements. 4. CONTRA-INDICATIONS: Hypersensitivity to
the active substance or to any of the excipients. 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Lantus is not the insulin of choice for the treatment of diabetic
ketoacidosis. Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin and/or method
of manufacture may result in the need for a change in dose. The warning symptoms of hypoglycaemia may be changed, less pronounced or absent in certain risk groups: for all
details see the full SmPC. If pioglitazone is used in combination with insulin, especially in patients with CHF risk factors, patients should be observed for signs and symptoms of
heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.6. DRUG INTERACTIONS: Substances that may
enhance or reduce the blood-glucose-lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. PREGNANCY AND LACTATION: No clinical
data from clinical trials are available. A moderate amount of data on pregnant women exposed indicates no adverse effects on pregnancy and no malformation nor feto/neonatal
toxicity. Lantus may be considered during pregnancy, if necessary. Breastfeeding women may require adjustments in insulin dose and diet. 8. EFFECTS ON ABILITY TO DRIVE:
Patients should take precautions to avoid hypoglycaemia whilst driving. 9. UNDESIRABLE EFFECTS: Hypoglycaemia may occur if the insulin dose is too high in relation to the
insulin requirement. Lipohypertrophy may occur at the injection site. Injection site reactions including redness, pain, itching, hives, swelling, or inflammation. For uncommon &
rare adverse events please consult the full SmPC. 10. OVERDOSAGE: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. More severe episodes
may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 11. PHARMACOLOGICAL PROPERTIES: ATC Code: A10A E04. 12. MARKETING
AUTHORIZATION HOLDER: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main. Abbreviated Prescribing Information based on the EU SmPC as of Jan 2011.
Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
- GLB.DIA.11.11.36 - 11/11
APIDRA® Abbreviated Prescribing Information. 1. NAME AND PRESENTATION: Apidra 100 U/ml, solution for injection of insuline glulisine is available in a vial of 10 ml, cartridge
of 3 ml for reusable devices Optipen, ClikSTAR, Autopen 24 or Tactipen & cartridge for Opticlik, and prefilled disposable pens of 3ml for Optiset & Solostar. 2.THERAPEUTIC
INDICATIONS: Treatment of adults, adolescents and children, 6 years or older with diabetes mellitus, where treatment with insulin is required. 3. POSOLOGY AND METHOD
OF ADMINISTRATION: Apidra should be given by subcutaneous injection shortly (0-15 min) before or soon after meals or by continuous subcutaneous pump infusion. Apidra
for injection in a vial can be administered intravenously. Apidra should be used in regimens that include an intermediate or long acting insulin or basal insulin analogue and
can be used with oral hypoglycaemic agents. The dosage of Apidra should be individually adjusted. For administration details see full SmPC. Patients must be educated to use
proper injection techniques and insulin label must always be checked before each injection to avoid medication errors between Apidra and other insulins. Renal impairment &
hepatic impairment: insulin requirements may be reduced. Elderly: deterioration of renal function may lead to a decrease in insulin requirements. 4. CONTRA-INDICATIONS:
Hypersensitivity to insulin glulisine or to any of the excipients. Hypoglycaemia. 5. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: Transferring a patient to a new type or
brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, source and/or method of manufacture may result in the need for a change in
dose. Concomitant oral antidiabetic treatment may need to be adjusted. Adjustment of dosage may be necessary if patients undertake increased physical activity or change their
usual meal plan. Conditions which may take the early warning symptoms of hypoglycaemia different or less pronounced are detailed in the full SmPC. Contains less than 1 mmol
sodium per dose. Contains metacresol. If pioglitazone is used in combination with insulin, especially in patients with CHF risk factors, patients should be observed for signs and
symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. 6. DRUG INTERACTIONS: Substances
that may enhance or reduce the blood-glucose-lowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. PREGNANCY AND LACTATION:
No adequate data are available. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Breast-feeding
mothers may require adjustements in insulin dose and diet. 8. ABILITY TO DRIVE: Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. 9.
UNDESIRABLE EFFECTS: Hypoglycaemia is the most frequent undesirable effect of insulin therapy. Injection site reactions and local hypersensitivity reactions. For uncommon
& rare adverse events, consult the full SmPC. 10. OVERDOSAGE: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. Severe
hypoglycaemic episodes can be treated by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously or by glucose given intravenously. 11. PHARMACODYNAMIC
PROPERTIES: ATC code: A10AB06. 12. MARKETING AUTHORIZATION HOLDER: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main. Abbreviated Prescribing
Information based on the EU SmPC as of January 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
INSUMAN®* Abbreviated Prescribing Information. 1. Name And Presentation: Insuman® (insulin human) 40 IU/ml or 100 IU/ml is a regular insulin solution (Rapid), or an
isophane insulin suspension (Basal) or biphasic isophane insulin suspension (Comb 15-25-30-50) consisting of 15%, 25% , 30%, or 50% dissolved insulin and complementary
portion of 85%, 75%. 70%, or 50% crystalline protamine insulin respectively. Insuman® is provided in a vial (5 or 10 ml) or cartridge (3 ml) for use with the reusable devices
OptiPen, ClikSTAR, Autopen 24 or Tactipen and cartridge for OptiClik or pre-filled disposable pens (3 ml) SoloSTAR and OptiSet. Insuman® is also available as injection vial
& cartridge for infusion (Insuman® Infusat 100 IU/ml). 2. Therapeutic Indications: Diabetes mellitus where treatment with insulin is required. Insuman® Rapid is suitable in
hyperglycaemic coma & ketoacidosis, as well as for pre-, -intra- and post-operative stabilisation in patients with diabetes mellitus. 3. Posology And Method Of Administration:
The dosage and timings should be individually adjusted. Daily doses and timing of administration: there are no fixed rules for insulin dose regimen. However, the average
insulin requirement is often 0.5 to 1.0 IU per kg body weight per day. Insuman® is injected subcutaneously 15 to 20 minutes (Rapid) or 45 to 60 minutes (Basal) or 30 to
45 minutes (Comb 15-25-30) or 20 to 30 minutes (Comb 50) before a meal. Insuman® Rapid for injection in a vial may also be administered intravenously (intensive care
conditions). Insuman® Basal and Comb must never be injected intravenously. Insuman® Infusat is used with an external pump, one part of the daily insulin dose is infused
continuously (“basal rate”), and the rest is administered in the form of bolus injections before meals. Refer to the infusion pump operating instructions for detailed information.
In the treatment of severe hyperglycaemia or ketoacidosis, insulin administration regimen requires close monitoring. Secondary dose adjustment: Improved metabolic control
may result in increased insulin sensitivity, leading to a reduced insulin requirement. Dose adjustment may also be required, if the patient’s weight or life-style changes. Other
circumstances arise that may promote an increased susceptibility to hypo- or hyperglycaemia. Patients must be educated to use proper injection techniques. For administration
details see full SmPC. Hepatic or renal impairment and elderly: insulin requirements may be reduced. 4. Contra-Indications: Hypersensitivity to the active substance or to any
of the excipients. Insuman® Rapid must not be used in external or implanted insulin pumps or in peristaltic pumps with silicone tubing. Insuman® Basal and Comb must not be
administered intravenously and must not be used in infusion pumps or external or implanted insulin pumps. Insuman® Infusat must not be used in peristaltic pumps with silicone
tubing. Refer to the technical manual for contraindications relating to the use of insulin pumps. 5. Special Warnings And Precautions For Use: Transferring a patient to another
type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin and/or method of manufacture may result in the need for
a change in dosage. Following transfer from an animal insulin to human insulin, dose regimen reduction may be required. The warning symptoms of hypoglycaemia may be
changed, less pronounced or absent in certain risk groups: for all details see the full SmPC. 6. Drug Interactions: Substances that may enhance or reduce the blood-glucoselowering activity and increase susceptibility to hypoglycaemia are detailed in the full SmPC. 7. Pregnancy And Lactation: No clinical data on exposed pregnancies are available.
Insulin does not cross the placental barrier. Caution should be exercised when prescribing to pregnant women. No effects on the suckling child are anticipated. Insuman® can
be used during breast-feeding. Lactating women may require adjustments in insulin dose and diet. 8. Effects On Ability To Drive: Patients should take precautions to avoid
hypoglycaemia whilst driving. 9. Undesirable Effects: Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Oedema, injection site
reactions. For uncommon & rare adverse events please consult the full SmPC. 10. Overdosage: Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates.
More severe episodes may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. 11. Pharmacodynamic Properties: ATC code:A10AC01.
12. Marketing Authorization Holder: Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Abbreviated Prescribing Information based on the EU SmPC
as of February 2011. Always refer to the full Summary of Product Characteristics (SmPC) before prescribing.
MANAGEMENT, CARE AND PREVENTION
Back to the future:
investigating new
treatments for type 1
diabetes using old
inexpensive drugs
Denise Faustman and Miriam Davis
"Great disappointments in medicine frequently give rise to great
innovation – so the saying goes – but who expected a 20-year
detour?" Denise Faustman and her team were disappointed by
their findings from human islet cell transplantation trials and
felt compelled to return to the bench for 20 years to understand
why the trials had been less successful than had been hoped.
They first turned to an animal model of type 1 diabetes, which,
just as in people, features an autoimmune assault on the
insulin-producing islet cells in the pancreas. The animal model
provided an opportunity to tease apart the immune system
that triggers the disease. Over the next 10 years, they turned
to studying the blood of large numbers of people with type
1 diabetes, hoping that the promising mouse data could be
replicated in people. Those years-long and human and mouse
studies suggested a new trigger for diabetes and, thus, a new
approach to designing a clinical trial to test a vaccine – a vaccine
we all hope will be an advance in treatment for people with type
1 diabetes, and if successful, a remarkably affordable one.
December 2011 • Volume 56 • Special Issue 2
More than 20 years ago, we began studying islet transplants in people with longstanding type 1 diabetes. We hoped to
replenish the pancreas with healthy islet
cells and thereby restore normal blood
glucose. To achieve this, we replaced
people’s islet cells with the same cells
modified to shield them from rejection
by their own immune system. In type 1
diabetes and other autoimmune diseases, the immune system regards some
tissues, such as the insulin-secreting islet
cells, as foreign, not part of the self, and
it erroneously rejects and destroys them.
At first, like many other islet transplant
researchers worldwide, we thought the
transplanted islet cells could be modified to escape the host's dysfunctional
immune attack when combined with
immunosuppressive drugs.
DiabetesVoice 37
MANAGEMENT, CARE AND PREVENTION
But we did not realize that the diseased
immune system was relentless: it continued to attack the newly transplanted
islet cells even decades after diagnosis of
the original disease. The autoimmunity
once again affected the transplanted
insulin-secreting cells, even when the
host received drugs to prevent kidney
rejection. We decided to take a step
back and turned to studying
how type 1 diabetes occurs
and how rogue white
blood cells are produced in the first
place.
At
first, we
used a wellknown rodent
model of type 1 diabetes
called the non-obese diabetic (NOD) mouse. We wanted to
learn more about the basic science
underlying type 1 diabetes in the hope of
finding more targeted ways to treat the
disease. At that time, little was known
about the kinds of rogue T cells that
caused type 1 diabetes – except that
they provoked a self-reactive and autoimmune disease. Laboratory-based
research using rodents does not attract
the interest that human clinical trials do
but it is the surest means to reveal the
complex disease processes.
The unusual suspects: CD8 T lymphocytes
Our first major breakthrough came in
1991, when we discovered that a new
type of immune cell was in part responsible for attacking the islet cells in the
pancreas – and this immune cell was not
the one most scientists pursued. Indeed,
other scientists received our finding
38
DiabetesVoice
with a degree of scepticism. We identified a major culprit as a type of immune
cell known as a CD8 T lymphocytes
(or CD8 T cells) in mice as well as and
humans.1 Other immune cells might
participate, but small, potent CD8 T
cells were a primary perpetrator.
Initially, we thought only people with diabetes had these disease-provoking CD8
T cells since when we studied identical
twins, only the twin with diabetes had
CD8 T cells. However, there are many
different types of CD8 T cells. In type
1 diabetes, only a particular subset of
CD8 T cells is defective – the subset that
targets specific proteins found almost
exclusively on the surface of islet cells.
The quest to find the abnormality in CD8
T cells lasted nearly a decade. In the late
1990s, we published our findings
that the educator cell of CD8 T
cells was defective and thus
the subset of rogue CD8
T cells might also
have similar proteins with the
defect.1
worldwide research had uncovered the
mechanism by which TNF usually does
not harm normal cells. However, the
mutant defective CD8 T cells in humans
and mice with diabetes became susceptible to specific killing, much like way
bacteria but not normal cells of the body
are vulnerable to antibiotics.2,3
We tested these findings first in tissue
culture with isolated cells from people
with diabetes, and showed, at albeit in
culture, evidence that TNF selectively
killed only the auto-reactive T cells.4 So
we hypothesized that TNF also could be
used as a treatment to destroy the abnormal CD8 T cells that caused type 1 diabetes, while sparing healthy cells. Simply
put, we hoped that TNF would act like a
laser-guided missile or an ‘antibiotic for
diabetes’. That was the rationale behind
our first experiments in NOD mice, then
later in human blood samples and now
in clinical trials.5,6
The
protein defects enabled the
abnormal CD8 T cell
to escape the process of ‘T
cell education’ – the process
of learning to be tolerant to cells
belonging to one’s own body.
So as they matured, poorly educated CD8 T cells attacked the body’s
own islet cells. But it turned out that
one of the dark clouds we had identified also had a silver lining: the CD8 T
cells became exquisitely vulnerable to
death by a normal protein of the immune
system known as tumour necrosis factor or TNF. We knew about TNF from
many basic science studies; previous
December 2011 • Volume 56 • Special Issue 2
Finding a fast track to the clinic
In engaging in clinical trials, our overarching aim is to develop only new therapies that are safe and widely affordable.
Clinical development is often very slow
but a short cut can save time and money
and ensure that safety is achieved at earlier
stages. Instead of directly administering
TNF, which is not an existing drug and
would require years of validated manufacturing processes, or testing it for safety
on live primates, we chose an indirect
method for TNF exposures that showed
us faster path to the clinic: we administered an agent that induced internal TNF
production using an 80-year-old vaccine
called Balcillus-Calmette-Guerin (BCG).
In 2001 and 2003, we published our
results showing that the TNF inducer
injected into end-stage diabetic animals
was capable of selectively killing the defective CD8 T cells responsible for killing
islet cells.5,6 The TNF inducer was an
old fashion vaccine that was originally
developed for protection from tuberculosis and treatment of bladder cancer. It
was so successful that after 15 weeks the
animals with diabetes began to produce
normal blood glucose levels for sustained
periods of time. For the first time, killing
rogue T cells using TNF was followed by
brisk islet regeneration. The concept that
diabetes might be treated by targeted disease removal was surprising and pleasing
news, especially since it worked even in
advanced disease.
That additional finding was first met with
widespread scepticism. Now, there is near
uniform acceptance of worldwide data
accumulated over the past eight years that
the pancreas can show growth well into
adulthood. Our results have been replicated in other animal models and in other
autoimmune diseases and there is enormous and growing interest in the many
different ways the pancreas can regenerate.
December 2011 • Volume 56 • Special Issue 2
The successes in killing the rogue T cells
and showing pancreas regeneration emboldened us to conduct experiments with
human blood samples. We studied blood
samples from 675 people with type 1
diabetes and 512 people without diabetes.
Using two different methods to measure
cell death in people with diabetes, we
showed that TNF killed a subpopulation of CD8 cells but did not kill a different population of T cells. The results
applied across all six different doses of
TNF.4 Furthermore, TNF was effective
in selectively killing rogue CD8 T cells
in several other autoimmune diseases.
TNF was effective in
selectively killing rogue
CD8 T cells in several
autoimmune diseases.
By this point, we felt ready to plan for a
human clinical trial with a TNF-inducer.
Unlike most other diabetes clinical trials, we focused on advanced type 1 diabetes. Our rationale was that if mice
with advanced type 1 diabetes could be
cured, we could choose people with the
greatest need for treatment. Moreover,
surmounting the toughest challenge
would be the most rigorous way to support our hypothesis that TNF could
selectively kill the disease-provoking T
cells. Our choice of BCG, an established
generic drug that was already on the
market, gave us two advantages: BCG’s
safety is very well established; the drug
would be inexpensive.
Our 20-year research programme had
established so many mechanisms about
the drug's effects that we were able to
monitor those throughout the trial to
ensure that BCG was working in the
manner and with the purpose intended.
This approach is known as translational
medicine with biomarkers: by closely
monitoring people’s blood, we are able
to determine whether the TNF is killing
the disease-provoking cells – like seeing
an antibiotic kill bacteria in the blood
of an person with an infection.
Real hope for the future
As we progress with the testing of BCG,
we hope to open up possibilities for treating people with long-standing diabetes
using a universally affordable drug. Data
from our Phase I trial, using only limited
doses of BCG and regular blood glucose
monitoring, are encouraging. Our aim is
to carry out these trials quickly and costefficiently in order to develop a cheap
generic drug for type 1 diabetes.
Denise Faustman and Miriam Davis
Denise Faustman is Director of Immunobiology at
the Massachusetts General Hospital and Harvard
Medical School, Immunbiology Laboratories,
Boston, USA. ([email protected])
Miriam Davis is a member of the Department
of Medicine at Massachusetts General
Hospital and Harvard Medical School,
Immunbiology Laboratories, Boston, USA.
References
1 F
austman D, Li X, Lin HY, et al. Linkage of faulty
major histocompatibility complex class I to
autoimmune diabetes. Science 1991; 254: 1756-61.
2 H
ayashi T, Faustman D. Defective function
of the proteasome in autoimmunity:
Involvement of impaired NF-kB activation.
Diabetes Tech Ther 2000; 2: 415-28.
3 H
ayashi T, Kodama S, Faustman DL. Reply
to 'LMP2 expression and proteasome activity
in NOD mice'. Nat Med 2000; 6: 1065-6.
4 B
an L, Zhang J, Wang L, et al. Selective death
of autoreactive T cells in human diabetes
by TNF or TNF receptor 2 agonism. Proc
Natl Acad Sci USA 2008; 105: 13644-9.
5 R
yu S, Kodama S, Ryu K, et al. Reversal
of established autoimmune diabetes
by restoration of endogenous beta cell
function. J Clin Invest 2001; 108: 63-72.
6 K
odama S, Kuhtreiber W, Fujimura S, et al. Islet
regeneration during the reversal of autoimmune
diabetes in NOD mice. Science 2003; 302: 1223-7.
DiabetesVoice 39
CAUSES AND EFFECTS
From victim to
protector – what
the brain does with
hypoglycaemia
Stephanie A Amiel
The human brain depends
on glucose to fuel all
its functions. Although
the brain can use other
metabolic substrates, and
babies’ brains do, glucose is its
normal energy source. As the brain
stores very little glucose, its proper function
depends on a reliable supply from its circulation.
If blood glucose concentrations fall too low, then
brain malfunction results. But what is the plasma
glucose concentration that is ‘too low’? Stephaine Amiel looks
into this surprisingly controversial topic.
40
DiabetesVoice
December 2011 • Volume 56 • Special Issue 2
CAUSES AND EFFECTS
We know that the plasma glucose at
which symptoms of hypoglycaemia occur is variable, depending heavily on a
person’s recent glycaemic experience, although the evidence suggests that some
degree of slowing of brain function is
detectable in everyone once plasma
glucose concentrations reach about
3 mmol/l (54 mg/dl). The American
Diabetes Association has recommended
that we consider any glucose concentration of less than 4 mmol/l (72 mg/
dl) as hypoglycaemia;1 the European
Medicines Agency less than 3 mmol/l
(54 mg/dl),2 elsewhere, less than 3.5
mmol/l (65 mg/dl) is considered diagnostic of a hypoglycaemic episode.
Universally, however, it is agreed that
people with diabetes using treatments
that can cause hypoglycaemia should
adjust their treatment regimens to
avoid frequent exposure to concentrations below 4.5 mmol/l (approximately 80 mg/dl). It is
certainly important to give
people a lower limit to any
glucose targets that we might
recommend to them – as well
as a higher limit!
cretion. The change in the insulin-toglucagon ratio in the blood leaving the
pancreas and going to the liver immediately switches on glucose production
by the liver cells, limiting the further
development of the hypoglycaemia. If
this does not work, and circulating glucose continues to fall, a more vigorous
stress response occurs with secretion
of stress hormones such as adrenaline
(epinephrine); stimulation of the autonomic nervous system (which acts
to increase the liver’s ability to make
glucose and also adjusts the circulation
to increase the blood flow to the brain)
and the release of other hormones to
help sustain the liver’s efforts and also
slow the rate at which muscle and fat
take glucose out of the circulation.
Research using brain imaging techniques have shown that during symp-
date memories from the preceding day.
Importantly, those brain regions that are
active when we are enjoying ourselves
are turned off by hypoglycaemia. Once
the hypoglycaemia is treated, brain areas involved in arousal, stimulated by
the low blood glucose, relax, perhaps
explaining why people feel sleepy after
an episode. Higher brain functions may
not be fully re-established for some 40
minutes after plasma glucose concentrations return to normal.
The protective stress responses to hypoglycaemia presumably evolved to
protect brain glucose supplies during times of food shortage, or when
muscle was using lots of glucose very
rapidly, perhaps as primitive humans
went chasing after lunch (or possibly
escaping from being lunch for someone
else). They efficiently protect the brain
from glucose deprivation
and make hypoglycaemia
severe enough to cause cognitive impairment very rare
in health.
The brain is the victim of
falling plasma glucose and
coordinator of the normal
protective response.
The brain is not just a victim
of falling plasma glucose; it
is also the coordinator of the normal
protective response. It is perhaps not
surprising that the body’s most important glucose sensors are placed in the
brain. Glucose-sensing neurones are
found throughout the brain stem and
most famously in the hypothalamus.
These neurones are activated by changes
in their glucose supply. When plasma
glucose falls, these neurones initiate and
coordinate a stress response that tends
to correct the situation.
The response starts with a message
to the pancreas to shut down insulin
production and increase glucagon se-
December 2011 • Volume 56 • Special Issue 2
tomatic hypoglycaemia, there is activation of the classical central stress
pathways (hypothalamus and pituitary),
hunger and appetite centres and also
areas of the brain that are involved in
monitoring how the body is behaving.3
Brain regions involved in aversion are
also stimulated. The brain seems able
to focus energy on these important
functions, and diverts attention from
such functions as memory and balance. Research suggests that people do
not make a memory for an event that
occurs when they are hypoglycaemic,
and if hypoglycaemia occurs during
sleep at night, they might not consoli-
For people with diabetes,
however, hypoglycaemia is
an all-too-familiar problem.
Especially in circumstances
of complete insulin deficiency (type 1
diabetes and late type 2 diabetes), defects
in the above protective responses to a
falling plasma glucose concentration allow the development of severe hypoglycaemia. Circulating insulin results from
insulin injection, and concentrations do
not fall just because the glucose concentration is falling. Because the cells
making glucagon are driven as much
by messages from insulin-secreting cells
stopping work, as by the low glucose
concentration itself, glucagon responses
to hypoglycaemia are also lost. People
with diabetes, therefore, depend most on
the rest of the stress response and, most
DiabetesVoice 41
CAUSES AND EFFECTS
importantly, the generation and perception of symptoms of hypoglycaemia:
stress symptoms and feelings of confusion and, importantly, hunger. Eating or
drinking readily available carbohydrate
is the best defence against a small hypoglycaemia becoming a big one.
Hypoglycaemia
unawareness is
associated with a sixfold increase in risk of
severe hypoglycaemia.
Sadly, for about a quarter of people
with longstanding type 1 diabetes and
an as yet undetermined number with
type 2 diabetes, defects develop in these
second-tier responses to hypoglycaemia.
As well as not being able to suppress
insulin or enhance glucagon, these
people mount feeble stress responses
that only start at much lower glucose
concentrations than usual. In this situation, the stress responses start after
the cognitive dysfunction has begun,
and the person experiencing the hypoglycaemia does not have the opportunity to make a proper response and
take carbohydrate before confusion and
reduced consciousness occur. This ‘hypoglycaemia unawareness’ is associated
with a six-fold increase in risk of severe
hypoglycaemia (by definition hypoglycaemia that is so severe the person needs
to be treated by someone else).4 There
is failure of activation of the brain’s
stress responses, and failure of activation of the symptom perception areas
too. Moreover, research suggests that
there is impaired shutdown of the reward circuitry and pleasure perception.
In some victims of unawareness, these
brain regions even may be stimulated!
We know that hypoglycaemia unawareness can be induced and maintained by
42
DiabetesVoice
recurrent exposure to modest hypoglycaemia in daily life. Equally, if a person
can adjust his or her diabetes therapy
to avoid dropping plasma glucose below 3 mmol/l (54 mg/dl) too often, or
for too long, the ability to perceive occasional subsequent hypoglycaemias
can be restored. Structured education
programmes (such as those described
on pages 16 to 28 of this special issue)
may help about half the participants
with hypoglycaemia unawareness to
regain awareness and they do reduce
the amount of severe hypoglycaemia
very substantially. It is thought that the
failure to perceive the unpleasantness of
each hypoglycaemia, as a result of the
altered response of reward circuitry and
pleasure perception, may block the other half from changing their behaviour
enough to avoid future hypoglycaemia
– rendering them resistant to the benefits of a purely educational approach.5
New strategies that help people change
behaviours for more healthy ones are
being developed.
We must improve
our ability to help
people with diabetes
to minimize their risk
for this distressing
complication of
diabetes therapies.
What of the long-term effects of hypoglycaemia on the human brain?
Again, neuroimaging and cognitive
function tests are being deployed to
determine whether recurrent hypoglycaemia has an impact on brain structure
and function. The data are reassuring
with regard to minor episodes, and
probably to even severe hypoglycaemia
in adults (as long as a full recovery is
made at the time) but there are growing
concerns that severe hypoglycaemia in
children with diabetes, which can be
complicated by seizures, may result in
impaired performance in some brain
functions tested later on.6 (An article
by Edith Schober and Reinhard Holl on
page 43 of this special issue explores the
links between diabetes and epilepsy in
young people.) There is no doubt that
we do need to improve on our ability
to help all of our patients with diabetes
to minimize their risk for this always
distressing and sometimes dangerous
complication of diabetes therapies.
Stephanie A Amiel
Stephanie A Amiel is RD Lawrence Professor of
Diabetic Medicine, King’s College London (UK).
References
1 E
uropean Medicines Agency, Committee for
Proprietary Medicinal Products. Note for guidance
on the clinical investigation of medicinal products
in the treatment of diabetes mellitus. www.ema.
europa.eu/docs/en_GB/document_library/
Scientific_guideline/2009/09/WC500003262.pdf
2 W
orkgroup on Hypoglycemia, American
Diabetes Association. Defining and reporting
hypoglycemia in diabetes: a report from the
American Diabetes Association Workgroup on
Hypoglycemia. Diabetes Care 2005; 28: 1245-9.
3 T
eh MM, Dunn JT, Choudhary P, et al.
Evolution and resolution of human brain
perfusion responses to the stress of induced
hypoglycemia. Neuroimage 2010; 53: 584-93.
4 S chopman JE, Geddes J, Frier BM. Frequency of
symptomatic and asymptomatic hypoglycaemia
in Type 1 diabetes: effect of impaired awareness
of hypoglycaemia. Diabet Med 2011; 28: 352-5.
5 S mith CB, Choudhary P, Pernet A, et al.
Hypoglycaemia unawareness is associated with
reduced adherence to therapeutic decisions in
patients with Type 1 diabetes: evidence from a
clinical audit. Diabetes Care 2009; 32: 1196-8.
6 N
ortham EA, Lin A. Hypoglycaemia in childhood
onset type 1 diabetes--part villain, but not the
only one. Pediatr Diabetes 2010; 11: 134-41.
December 2011 • Volume 56 • Special Issue 2
CAUSES AND EFFECTS
Epilepsy in children
and adolescents with
type 1 diabetes
Edith Schober and Reinhard Holl
Seizures provoked by
hypoglycaemia are relatively
frequent in people with type 1
diabetes. Each year, up to
15% of children with type 1
diabetes experience a severe
hypoglycaemic episode, or
‘hypo’, with seizures – often as a
result of administering too much
insulin. But seizures also can
occur during diabetic ketoacidosis
– when not enough insulin
has been taken. These acute
complications often constitute
an obstacle to diagnosis of
epilepsy in people, especially
children and adolescents, with
diabetes. The authors of this
article look at some of the links
between epilepsy and type 1
diabetes and report on a number
of interesting findings from
their recent study involving
a large number of European
children with type 1 diabetes.
December 2011 • Volume 56 • Special Issue 2
Epilepsy is a common chronic neurological condition, which affects the
nervous system. Also referred to as
a ‘seizure disorder’, epilepsy involves
sporadic electrical storms in the brain,
which cause sudden mild loss of attention or staring, and/or violent muscle
contractions and loss of consciousness,
known as grand mal seizures. There
are several types of epilepsy, each with
different causes, symptoms and treatments. Idiopathic generalized epilepsy is
a group of disorders that tends to manifest itself in young people between early
childhood and adolescence but which
can develop in later life. The prevalence
of idiopathic generalized epilepsy varies
according to age. A peak prevalence of
1.1% occurs in adults over 50 years of
age; in children and adolescents, the
prevalence of epilepsy ranges between
0.2% and 0.4%.1
There is a recognized association between diabetes and idiopathic generalized epilepsy. In a UK study, a group
of adults with epilepsy were found to
have a four-fold higher prevalence of
type 1 diabetes compared to the general
population.2 In that group, diagnosis
of diabetes had preceded the onset of
epilepsy by several years.
Epilepsy-related
seizures in children
may be mistaken
for symptoms of
hypoglycaemia.
Recent studies in children have showed
conflicting results. An Italian centre reported a higher prevalence of epilepsy in
adolescents with diabetes compared to
young people without diabetes. Again,
diabetes had been diagnosed in these
young people on average 2.8 years before epilepsy.3 On the other hand, an
Australian study found no increase in
risk for epilepsy in children and adolescents with diabetes.4
In many cases, epilepsy-related seizures in
children may be mistaken for the symptoms of hypoglycaemia. Consequently,
the diagnosis of epilepsy in children with
diabetes is often delayed or underestimated. Generally, a diagnosis of epilepsy
is based on at least two unprovoked seizures – not resulting from an external
cause, such as injury or consumption of
DiabetesVoice 43
CAUSES AND EFFECTS
frequency of epileptic seizures in children and adolescents with diabetes than
expected: twice as high as in children
without diabetes. There was no difference between boys and girls.
We found a significantly
higher frequency of
epileptic seizures
in children and
adolescents with
diabetes than expected.
prescribed medications or other drugs –
in a person with normal blood glucose
levels (above 3.9 mmol/l) and with an
interval greater than 24 hours between
the seizures. Although monitoring blood
glucose is recommended when seizures or
loss of consciousness occur in a child with
diabetes, parents might not carry out a
glucose test in such a frightening situation.
It could it be that people
with repeated episodes
of ketoacidosis are
more prone to epilepsy.
We had the opportunity to analyze
the association between diabetes and
epilepsy in a large group (45,847) of
young people with type 1 diabetes aged
between 0.1 and 20 years from Germany
and Austria as part of the DPV initiative.5 We found a significantly higher
44
DiabetesVoice
Some interesting findings
It was interesting to note that the children with both diabetes and epilepsy
were younger at onset of diabetes than
the children with diabetes alone. The
reason for the increased frequency of
epilepsy in children with type 1 diabetes
is unknown and deserves further investigation. However, previous studies have
shown that both severe hypoglycaemia
and ketoacidosis can lead to abnormalities in an electroencephalogram (test to
detect problems in the electrical activity
of the brain) in children with diabetes.
Given the risk of acute complications
posed by both diseases, parents of children with epilepsy and diabetes might be
expected to prevent convulsions in their
child by attempting to avert hypoglycaemia using less insulin – with the consequence of higher overall blood glucose
levels. However, among the children with
both diseases, HbA1c levels and insulin dosage-to-body weight ratios were
similar to those in the children without
epilepsy and we saw no difference in the
type of treatment – pump or injections.
An interesting and unexplained result of
our study was a significantly increased
risk for diabetic ketoacidosis in children
and adolescents with type 1 diabetes and
epilepsy. They appear to be at twice the
risk compared to children with type 1
diabetes alone. The causes of this association are unclear. It could it be that
people with repeated episodes of ketoacidosis are more prone to epilepsy.
Education to prevent complications
Close observation by parents of a child
with diabetes and epilepsy could enable
them to anticipate the symptoms of
metabolic disturbances, allowing earlier
diagnosis of (still mild) ketoacidosis. In
reality, however, we found that rates of
mild as well as severe ketoacidosis were
higher in the children with both diseases. Children, their families and their
healthcare providers need to be aware
of this increased risk and should receive
adequate and appropriate education to be
able to detect and prevent ketoacidosis.
Edith Schober and Reinhard Holl
Edith Schober is paediatric diabetologists in the
Department of Paediatrics and Adolescent Medicine,
Division of Paediatric Pulmology, Allergology and
Endocrinology, Medical University Vienna, Austria.
Reinhard Holl is paediatric diabetologist and
epidemiologist at the Institute of Epidemiology and
Medical Biometry, University of Ulm, Germany.
References
1 M
artinez C, Sullivan T, Hauser WA. Prevalence
of acute repetitive seizures (ARS) in the United
Kingdom. Epilepsy Res 2009; 87: 137-43.
2 M
cCorry D, Nicolson A, Smith D, et al.
An Association between Type 1 Diabetes
and Idiopathic Generalized Epilepsy.
Ann Neurol 2006; 59: 204-6.
3 M
ancardi MM, Striano P, Giannattasio A, et
al. Type 1 diabetes and epilepsy: More than a
casual association? Epilepsia 2010; 51: 319-322.
4 O
’Connell MA, Harvey AS, Mackay MT,
Cameron FJ. Does epilepsy occur more frequently
in children with Type 1 diabetes?
J Paediatr Child Health 2008; 44: 586-9.
5 S chober E, Otto KP, Dost A, et al for the
German/Austrian DPV Initiative and the BMBF
competence network diabetes. Association
of epilepsy and type 1 diabetes in children
and adolescents. Is there an increased risk
for DKA? Journal of Pediatrics (in press).
December 2011 • Volume 56 • Special Issue 2
Diabetes champions
Breakthrough – the
story of Elizabeth
Hughes and the making
of a medical miracle
Arthur Ainsberg
Of the many medical innovations
seen in the 20th century, few
were so pivotal as the discovery
of insulin for the treatment for
diabetes. A newly published
book, Breakthrough, tells the
story of a young girl who should
have died as a child but survived
to see seven grandchildren,
and the drug that, for millions
worldwide, has turned a death
sentence into something more
like a chronic irritation. A portion
of the book’s proceeds is going to
IDF’s Life for a Child Programme.
The authors tell us more.
December 2011 • Volume 56 • Special Issue 2
Since its discovery in 1921, insulin has
become the most widely prescribed drug
in history. Many of the world’s estimated
366 million people with diabetes rely
on this life-saving treatment. Although
for millions administration of the drug
has become a normal part of life, its
discovery by four men at the University
of Toronto – Frederick Banting, Charles
Best, John James Rickard Macleod,
James Collip – was anything but ordinary. They endured countless setbacks,
disappointments and betrayals – even
a fistfight! – before they discovered
an effective extract. Their discovery
transformed the life of nearly everyone around them, including their own.
In 1920, Frederick Banting presented
his idea for a diabetes treatment to John
James Rickard Macleod at the University
of Toronto. Banting believed that by tying off part of a dog’s pancreas, its tissues
would degenerate and allow him to isolate a secretion that people with diabetes
needed to survive. Although the process
had been tried before, the recent advent of sophisticated glucose monitoring
methods would allow Banting to test
accurately the effects of his treatment.
Though cautious, Macleod granted him
a research lab and assigned Best as his
assistant. Neither Banting nor Best
was a premier scientist or researcher.
Banting had been a mediocre student
at the University of Toronto’s Medical
School and served as a medic in World
War I. Best was a college student hoping
for experience in a research lab.
At the same time, an adolescent girl
would be relying on the success of these
two unlikely heroes. Elizabeth Hughes
was the youngest daughter of one of the
USA’s most famous politicians at that
time, Charles Evans Hughes.
To this day, her father remains the only
man in American history to have served
as New York Governor, US Secretary
of State, Associate Justice and Chief
Justice of the Supreme Court. In 1919,
11-year-old Elizabeth was diagnosed
with ‘juvenile’ diabetes, now known as
type 1 diabetes. Her prognosis looked
grim. Before insulin, children with type 1
DiabetesVoice 45
Diabetes champions
diabetes survived an average of 11
months after diagnosis; from 1900 to
1919, half of all people with diabetes
died within two years.
Elizabeth’s parents turned to Frederick
Allen, known then as a premier diabetes expert. Allen’s ‘starvation diet’ was
one of the more effective treatments to
prolong the short life of a person with
diabetes. Before diabetes, Elizabeth’s
recommended daily caloric intake
was 2,200 calories; on the Allen diet,
she sometimes dipped as low as 400.
Incredibly, Elizabeth adhered perfectly
to Allen’s diet, never wavering in her
belief that if she could just stay alive long
enough, a breakthrough would occur
that would save her from this disease.
If Elizabeth could just
stay alive long enough,
a breakthrough would
occur that would save
her from this disease.
46
turned her down. Insulin was simply too
experimental and too scarce.
To meet the demand for mass manufacturing, the Toronto team entered
into a partnership with Eli Lilly and
Company – a radical idea at the time.
However, insulin remained an unstable,
experimental drug. People with diabetes
continued to die.
Elizabeth Hughes was to be one of
the lucky ones. On 15 August 1922,
Elizabeth, sat in Banting’s office in
Toronto, became one of the first people
to receive an insulin injection. Though
initial supplies were sparse and dangerous, potentially deadly even, Elizabeth
flourished. She gained weight quickly
and grew taller, changes she described
as “unspeakably wonderful”.
As Elizabeth wasted away, progress was
being made in Toronto. Banting and
Best’s new extract, which they named
insulin, kept a dog with diabetes alive for
20 days. Researchers around the world
began to take notice. With this new success, Macleod was finally convinced
that Banting’s and Best’s discovery was
worthy of a research team.
From the first failed experiment to its
worldwide launch, insulin was developed in two years. Today, a new drug
takes approximately 12 years and USD
1 billion to reach the end user (patient) –
after successfully completing a series of
government and regulatory reviews. But
insulin is not a cure. It does not prevent
or eradicate diabetes nor does it prevent the development of disabling and
life-threatening complications. Insulindependent people with diabetes need
to take great care in monitoring and
managing their health.
The beginning of 1922 would pass in a
whirlwind. Researchers lost the ability
to make an effective extract; Banting, believing others were trying to take credit
for his work, temporarily withdrew from
the research team and began drinking heavily; Elizabeth Hughes’ weight
dropped to 19.5 kg (43 lb). Her mother,
desperate for help, wrote to Banting
asking him to treat her daughter. As
he did with all other requests, Banting
As we approach the 90th anniversary
of the discovery of insulin, it is important to reflect on the importance of the
drug and how much treatment options
have changed since its inception. After
centuries of ill-advised and even dangerous recommendations, insulin was the
first truly effective treatment for people
living with type 1 diabetes. It did not
briefly delay an untimely, horrific death;
it helped people to live normal, full lives.
DiabetesVoice
The lives of Elizabeth Hughes
Three months after Frederick
Banting injected her with insulin,
Elizabeth Hughes left Toronto to begin a new life. It had been her dream
to live as a normal girl, and insulin
allowed her to live that dream – as
long as she kept her diabetes a secret. That was no mean feat, given
the demands of diabetes management, and this was long before the
conveniences of glucose monitors
and disposable syringes. Yet through
exceptional determination and discipline, she succeeded in living the
extraordinary, ordinary life that she
had longed for during her agonizing,
pre-insulin years of starvation.
Just as remarkable as Elizabeth
Hughes’s ‘disappearance’ in 1922,
was the way that she re-emerged,
after some 43,000 injections of insulin, 58 years later. This is recounted
in Michael Bliss’s book, The Discovery
of Insulin. Bliss, understandably,
assumed that Elizabeth was dead
and wrote to Elizabeth’s husband,
William Gossett, hoping to obtain
some information about her later
years. Imagine his surprise when the
reply came from Elizabeth herself!
She was distressed that Bliss had
found her and agreed to talk only
after he promised to provide her with
an alias in his book. Even her own
children did not know of her diabetes
until they were 18 years old.
Among people with diabetes today,
there are varying opinions about how
public or private one should be in
the quotidian management of diabetes. Some advocate injections at
the dinner table; others adhere to a
policy of privacy. Such debates were
impossible before insulin. Whether
or not one agrees with Elizabeth’s
choice, one cannot help but appreciate her remarkable life – or one
might say lives.
Thea Cooper
Arthur Ainsberg
Arthur Ainsberg , with Thea Cooper, is
the co-author of Breakthrough - Elizabeth
Hughes, the discovery of insulin, and
the making of a medical miracle.
December 2011 • Volume 56 • Special Issue 2
Diabetes champions
In the race for a
glittering prize – Team
Type 1 hits the road
Phil Southerland
Many people are shocked when I say that my
diabetes is a gift – or that I would not take
a cure if it were offered to me. But that
is the truth. Diabetes is my life; I would
not trade it for the world. Because of
diabetes, I am healthier today than I
would have been without the disease.
Because of diabetes I live an incredible
life – beyond my dreams – as the founder
and chief executive officer of Team Type 1,
a USA-based professional cycling team.
Because of diabetes, I am able to play a part
in helping to make life better for millions of
people around the world. At Team Type 1, our
goal is to show people that not only can people
live their dreams with diabetes, but that diabetes
combined with the resources and diligence it takes to
manage the condition properly can be a path to achieving
success in all aspects of life.
Team Type 1 was conceived and established because of my friend, Joe
Eldridge. When we met in college, Joe
was not managing his diabetes well at
all. To encourage him to do better, we
December 2011 • Volume 56 • Special Issue 2
made a sporting bet: at the end of the
school day, the higher blood sugar pays
for dinner. Joe bought me a lot of burritos
that semester! But one day, the burritos
stopped coming and Joe said, "Thank you
DiabetesVoice 47
Diabetes champions
for saving my life." That was the ‘game
changer’ for me.
Joe told me I was his hero; as far as I was
concerned, he was the hero: he had taken
control of his diabetes and his life. I grew
up without a diabetes role model; diabetes
had always seemed to me like a disease
with no heroes. But I knew that Joe could
be a powerful inspiration. We both liked
cycling and I thought the bike could be
a great platform to reach and motivate
young people. Maybe we could provide
a few diabetes heroes…
Prejudice and ignorance
forces many people
around the world
are forced to hide
their diabetes.
Team Type 1 – we work to inspire
A global sports organization was born out
of that idea. Team Type 1-SANOFI has a
world-class athletic programme with approximately 100 cyclists, runners and triathletes – more than 60 with type 1 diabetes
and more than 20 with type 2 diabetes – all
competing at the highest levels in their
sports. We work to inspire. We train and
compete against some of the best athletes
on the planet to demonstrate to our peers
everywhere that they can achieve their
dreams if they can manage their condition and control their blood glucose, and
to encourage others to take up physical
exercise to prevent type 2 diabetes.
I travel widely with Team Type 1 and
have met people striving to live with
diabetes in such countries, who, before
meeting our athletes, have little hope
for the future. When they see what our
athletes have achieved and tell me of their
newfound optimism, I feel a strong emotion that is difficult to measure or even
describe. Whether I talk to a group of
48
DiabetesVoice
children or a room full of government
officials, many audiences find it very
hard to believe that I was diagnosed 29
complication-free years ago and that our
athletes with type 1 diabetes are competing and winning in world-class events.
"But you look normal", people say. And
I reply that that is because we are normal
– when we have the tools and education
we need to control our disease we are.
tion in Macedoina will have, for the first
time, free access to insulin and test strips.
It is not a huge population but as a wise
man once said, even the longest journey
must begin with a single step. And for
2,500 people with diabetes, that journey
now has very a different look to it.
Diabetes advocates at the top of their
game
Team Type 1 has a crucial role to play
in advocating for the rights of people
with diabetes. In the USA, people with
diabetes have access to the supplies and
medication we need, enabling us to live
a healthy productive life without limitations – a basic human right. But that is
not the case for the millions of people
worldwide who do not have access to
life-saving supplies. What is more, in
many countries, outmoded and offensive
discriminatory policies and widespread
diabetes unawareness conspire to prevent
people with the condition from attending
school or having a job or even having a
life partner. No wonder so many people
around the world hide their diabetes –
they are forced to.
We are bringing a powerful message that
we hope will be the global game changer
– for people with diabetes, people without
diabetes, whole communities, employers,
politicians and policy makers and media
and diabetes stakeholders everywhere: if
you have the right medicine, test strips and
a decent meter and you know how to use
them properly, diabetes is not a sickness;
diabetes is a lifestyle.
In arenas of sporting excellence and at
diabetes meetings and events worldwide, Team Type 1 is fighting to take
the stigma out of diabetes and adding
our voice to the global movement that
is effectively pressuring governments to
take real steps to improve the lives of their
citizens with diabetes. During a recent
trip to Macedonia, where I gave a presentation in the lead-up to the September
2011 UN High-Level Meeting on NCDs,
representatives of the Ministry of Health
requested a meeting at which they agreed
to fund essential diabetes supplies. As a
result, the entire type 1 diabetes popula-
Diabetes is not a sickness;
diabetes is a lifestyle.
Eyes on the prize
The recent UN summit was a step in the
right direction but much work remains to
be done. By continuing to offer an example, pushing the boundaries of possibility
with diabetes and promoting education
and empowerment, we intend to keep
the diabetes advocacy pedals turning, to
maintain the momentum of IDF’s campaign for recognition of diabetes and
other NCDs at the very highest levels.
Phil Southerland
Phil Southerland is founder and CEO
of Team Type 1. He is also an IDF Blue
Circle Champion.
December 2011 • Volume 56 • Special Issue 2
Diabetes champions
From diabetes
education and
prevention all the way
to sporting excellence –
Italy’s BCD Campaign
Massimo Massi-Benedetti
Great strides have been made in our collective
understanding of the benefits of well-managed
diabetes and controlled blood glucose, and the
key role in these that is played by physical activity.
Yet slow progress has been made translating this
knowledge into effective lifestyle education to
engender healthful behaviour on a large scale.
Very many young people remain at particularly high
risk from the chronic effects of disabling diabetes
complications. The threat of huge increases in the
human and economic costs of diabetes demands a
concerted response by multiple sectors of society
to spot the warning signs and reduce the multiple
health risks associated with this life-long condition.
Massimo Massi-Benedetti describes a countrywide
initiative in Italy, Campagna Buon Compenso del
Diabete (BCD Campaign), which aims to spread
a culture of diabetes prevention through healthy
lifestyle education.
December 2011 • Volume 56 • Special Issue 2
The BCD Campaign is promoted by the International Diabetes
Federation along with Italy’s professional diabetes organizations, the Association of Diabetologists (AMD) and the
Italian Diabetology Association (SID), and groups representing people with diabetes, the Italian Diabetes Association
(FAND-AID) and the Italian Association for Sports and
Diabetes (ANIAD). The Campaign is supported by the Italian
Association of Paediatric Endocrinology and Diabetology and
the Ministry of Health and financed by Sanofi Italy.
The BCD Campaign promotes multiple
partnerships involving a broad range
of players in the fight against diabetes.
The Campaign programme is a vehicle for activities that raise
awareness by sharing information on prevention, control and
treatment of diabetes through lifestyle education – with a
special focus on sporting activities. The Campaign promotes
multiple partnerships involving a broad range of players in
the fight against diabetes: the medical-scientific community,
institutions and healthcare professionals, volunteer associations, sports associations and the media.
DiabetesVoice 49
Diabetes champions
The AC Milan goalkeeper, Christian Abbiati (close up), who took part in
several BCD activities. Young campers gather for a hike (main photo).
Since its inception in 2008, the BCD Campaign has reached
more than 200,000 people in 80 Italian towns and cities, as
well as major Italian companies and public institutions, carrying out screening and free tests (blood glucose, HbA1c, blood
pressure, BMI) to assess people’s cardiometabolic risks, and
providing them with educational materials. To date, some
14,000 visits have been conducted, involving 600 institutions, and 170,000 brochures distributed. More than 2,700
press articles and citations have given the BCD Campaign
a visibility equivalent to nearly 360 million media contacts.
People with diabetes can participate in any sporting activities,
even at the very highest levels.
The Campaign supports a range of sporting projects that
carry a key message: when diabetes is managed well, it is
not an obstacle; people with diabetes can participate in any
sporting activities, even at the very highest levels. A new BCD
project, Diabetes and Sports, aims to turn this message into
reality for young people with diabetes in Italy. The project
is the fruit of partnerships with the elite endurance sports
outfit, Team Type 1 and the football club, AC Milan, via their
Foundation. (An article on page 47 by the Team’s founder,
Phil Southerland describes the origins aims and activities of
Team Type 1). Thanks to these collaborations, 70 children
50
DiabetesVoice
with diabetes have the opportunity to spend a week at one
of AC Milan’s residential summer camps, where ideal conditions have been created to guarantee children with diabetes
(selected by Italian Association of Paediatric Endocrinology
and Diabetology) the opportunity to train safely every day
alongside children without diabetes.
As you would expect from the best summer camps anywhere,
the Milan camps provided a comprehensive range of sporting
and leisure activities, as well as a social programme to fuel the
bonding process among the children and promote empathy
and self-confidence. The initiative has proved popular among
the medical community and families, and has become a top hit on the
Internet. Within days of the camps
opening, the family members of children with diabetes began exchanging
comments and writing blogs. Their
general impression was very positive.
Massimo Massi-Benedetti
Massimo Massi-Benedetti is Chair of the IDF Science Task Force.
December 2011 • Volume 56 • Special Issue 2
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